141 results on '"Rother"'
Search Results
2. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria
- Author
-
Hillmen, Peter, Muus, Petra, Dührsen, Ulrich, Risitano, Antonio M., Schubert, Jörg, Luzzatto, Lucio, Schrezenmeier, Hubert, Szer, Jeffrey, Brodsky, Robert A., Hill, Anita, Socié, Gerard, Bessler, Monica, Rollins, Scott A., Bell, Leonard, Rother, Russell P., and Young, Neal S.
- Published
- 2007
- Full Text
- View/download PDF
3. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria
- Author
-
Hill, Anita, Hillmen, Peter, Richards, Stephen J., Elebute, Dupe, Marsh, Judith C., Chan, Jason, Mojcik, Christopher F., and Rother, Russell P.
- Published
- 2005
- Full Text
- View/download PDF
4. Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti–DC-SIGN antibody
- Author
-
Tacken, Paul J., de Vries, I. Jolanda M., Gijzen, Karlijn, Joosten, Ben, Wu, Dayang, Rother, Russell P., Faas, Susan J., Punt, Cornelis J.A., Torensma, Ruurd, Adema, Gosse J., and Figdor, Carl G.
- Published
- 2005
- Full Text
- View/download PDF
5. A novel mechanism of complement-independent clearance of red cells deficient in glycosyl phosphatidylinositol–linked proteins
- Author
-
Jasinski, Marek, Pantazopoulos, Panagiotis, Rother, Russell P., van Rooijen, Nico, Song, Wen-Chao, Molina, Hector, and Bessler, Monica
- Published
- 2004
- Full Text
- View/download PDF
6. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria
- Author
-
Petra Muus, Leonard Bell, Antonio M. Risitano, Lucio Luzzatto, Hubert Schrezenmeier, Peter Hillmen, Gérard Socié, Jeff Szer, Ulrich Dührsen, Robert A. Brodsky, Neal S. Young, Monica Bessler, Scott A. Rollins, Jörg Schubert, Russell P. Rother, Anita Hill, Hillmen, P, Muus, P, Duhrsen, U, Risitano, ANTONIO MARIA, Schubert, J, Luzzatto, L, Schrezenmeier, H, Szer, J, Brodsky, Ra, Hill, A, Socie, G, Bessler, M, Rollins, Sa, Bell, L, Rother, Rp, and Young, N. S.
- Subjects
Hemolytic anemia ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Immunology ,Hemoglobinuria, Paroxysmal ,Pilot Projects ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Gastroenterology ,Hemolysis ,Complement inhibitor ,Translational research [ONCOL 3] ,Interventional oncology [UMCN 1.5] ,Risk Factors ,Internal medicine ,Thromboembolism ,medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,Antibodies, Monoclonal ,Cell Biology ,Hematology ,Complement System Proteins ,Eculizumab ,Middle Aged ,medicine.disease ,Surgery ,Complement Inactivating Agents ,Embolism ,Paroxysmal nocturnal hemoglobinuria ,Hemoglobinuria ,Female ,Hemoglobinemia ,business ,Complication ,medicine.drug ,Follow-Up Studies - Abstract
Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n = 195); patients from these studies continued treatment in the current multinational open-label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317).
- Published
- 2007
- Full Text
- View/download PDF
7. Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody
- Author
-
Gosse Jan Adema, Ruurd Torensma, I. Jolanda M. de Vries, Susan J. Faas, Paul J. Tacken, Ben Joosten, Dayang Wu, Karlijn Gijzen, Carl G. Figdor, Cornelis J. A. Punt, Russell P. Rother, and Other departments
- Subjects
T cell ,Recombinant Fusion Proteins ,T-Lymphocytes ,Immunology ,chemical and pharmacologic phenomena ,Receptors, Cell Surface ,T-Cell Antigen Receptor Specificity ,Humanized antibody ,Major histocompatibility complex ,Protein Engineering ,Biochemistry ,Epitope ,Antibodies ,Antigen ,Immune Regulation [NCMLS 2] ,Translational research [ONCOL 3] ,medicine ,Humans ,Lectins, C-Type ,Antigens ,Antigen Presentation ,Vaccines ,biology ,Hereditary cancer and cancer-related syndromes [ONCOL 1] ,Immunity ,hemic and immune systems ,Immunotherapy, gene therapy and transplantation [UMCN 1.4] ,Cell Biology ,Hematology ,Dendritic cell ,Dendritic Cells ,Tissue engineering and pathology [NCMLS 3] ,DC-SIGN ,Pathogenesis and modulation of inflammation [N4i 1] ,medicine.anatomical_structure ,Hemocyanins ,biology.protein ,Immunotherapy ,Cell Adhesion Molecules ,Keyhole limpet hemocyanin ,Immunity, infection and tissue repair [NCMLS 1] - Abstract
Contains fulltext : 48062.pdf (Publisher’s version ) (Open Access) Current dendritic cell (DC)-based vaccines are based on ex vivo-generated autologous DCs loaded with antigen prior to readministration into patients. A more direct and less laborious strategy is to target antigens to DCs in vivo via specific surface receptors. Therefore, we developed a humanized antibody, hD1V1G2/G4 (hD1), directed against the C-type lectin DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) to explore its capacity to serve as a target receptor for vaccination purposes. hD1 was cross-linked to a model antigen, keyhole limpet hemocyanin (KLH). We observed that the chimeric antibody-protein complex (hD1-KLH) bound specifically to DC-SIGN and was rapidly internalized and translocated to the lysosomal compartment. To determine the targeting efficiency of hD1-KLH, monocyte-derived DCs and peripheral blood lymphocytes (PBLs) were obtained from patients who had previously been vaccinated with KLH-pulsed DCs. Autologous DCs pulsed with hD1-KLH induced proliferation of patient PBLs at a 100-fold lower concentration than KLH-pulsed DCs. In addition, hD1-KLH-targeted DCs induced proliferation of naive T cells recognizing KLH epitopes in the context of major histocompatibility complex (MHC) classes I and II. We conclude that antibody-mediated targeting of antigen to DCs via DC-SIGN effectively induces antigen-specific naive as well as recall T-cell responses. This identifies DC-SIGN as a promising target molecule for DC-based vaccination strategies.
- Published
- 2005
8. SUSTAIN: A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 12-Month Study to Assess Safety and Efficacy of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises
- Author
-
Ataga, Kenneth I., primary, Kutlar, Abdullah, additional, Kanter, Julie, additional, Liles, Darla, additional, Cancado, Rodolfo, additional, Friedrisch, João, additional, Guthrie, Troy H., additional, Knight-Madden, Jennifer, additional, Alvarez, Ofelia A., additional, Gordeuk, Victor R., additional, Gualandro, Sandra, additional, Collela, Marina Pereira, additional, Smith, Wally R., additional, Rollins, Scott A., additional, Stocker, Jonathan W., additional, and Rother, Russell P., additional
- Published
- 2016
- Full Text
- View/download PDF
9. SUSTAIN: A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 12-Month Study to Assess Safety and Efficacy of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises
- Author
-
Julie Kanter, Kenneth I. Ataga, Marina Pereira Collela, Sandra Fátima Menosi Gualandro, Russell P. Rother, Wally R. Smith, Troy H. Guthrie, Rodolfo D. Cançado, Darla K. Liles, Victor R. Gordeuk, Jonathan W. Stocker, Scott A. Rollins, Ofelia A. Alvarez, Abdullah Kutlar, Jennifer Knight-Madden, and Joao Ricardo Friedrisch
- Subjects
0301 basic medicine ,myalgia ,education.field_of_study ,medicine.medical_specialty ,Randomization ,business.industry ,Immunology ,Population ,Cell Biology ,Hematology ,Chest pain ,medicine.disease ,Placebo ,Biochemistry ,Sickle cell anemia ,Acute chest syndrome ,03 medical and health sciences ,030104 developmental biology ,Internal medicine ,Medicine ,medicine.symptom ,business ,Adverse effect ,education - Abstract
Introduction: Acute painful episodes, frequently called sickle cell-related pain crises (SCPC), are a substantial cause of morbidity in sickle cell disease (SCD). Although hydroxyurea (HU) is known to decrease the frequency of SCPC in sickle cell anemia, many patients continue to experience acute painful episodes despite such therapy. P-selectin is an adhesion molecule expressed on activated vascular endothelial cells and platelets. It is a key molecule in the initiation of leukocyte rolling on the vessel wall that leads to firm attachment and extravasation to underlying tissues during inflammation. Upregulation of P-selectin on endothelial cells and platelets also contributes to the cell-cell interactions involved in the pathogenesis of SCPC. The SUSTAIN study evaluated the safety of SelG1, a first-in-class humanized anti-P-selectin antibody, and its effect on the frequency of SCPC in SCD patients. Methods: We conducted a randomized, double-blind, placebo-controlled, multinational study. Patients were randomized to receive placebo, 2.5 mg/kg or 5.0 mg/kg SelG1; patients received their initial dose, a dose 14 days later, and then every 4 weeks through week 50 for a total of 14 doses. The primary efficacy endpoint was the annual rate of SCPC in the 5.0 mg/kg SelG1 group vs. placebo. A hierarchical testing procedure was employed (α = 0.05 for high dose vs. placebo, and if significant, low dose vs. placebo). An SCPC was defined as acute sickle cell-related pain that resulted in a visit to a medical facility and required a parenteral or oral narcotic or parenteral NSAID. Acute chest syndrome (ACS), priapism, hepatic and splenic sequestration were also included in this definition. A blinded, independent committee adjudicated all SCPC events. Key inclusion criteria included patients 16 to 65 years of age; diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia or HbSβ+ thalassemia); and history of 2 to 10 SCPC in the previous 12 months. Patients receiving HU or erythropoietin were included if prescribed for the preceding 6 months and dose was stable for at least 3 months. The randomization was stratified by historical SCPC in the prior year (2-4 or 5-10) and concomitant HU use (yes or no). Secondary endpoints included annual rate of days hospitalized, times to first and second SCPC and annual rate of uncomplicated SCPC (defined as typical SCPC other than ACS, priapism and hepatic or splenic sequestration) and ACS. Results: 198 SCD patients were randomized for the 1-year study. The Intent-To-Treat (ITT) population included all randomized patients; 67, 66 and 65 patients in the 5.0 mg/kg, 2.5 mg/kg and placebo groups, respectively. Demographic parameters were evenly distributed in the treatment groups. The primary endpoint, the annual rate of SCPC in the ITT population at 5.0 mg/kg vs. placebo, was reduced 47% (medians of 1.6 vs. 3.0, p = 0.010, Table 1). The SelG1 drug effect was dose-dependent as the annual rate of SCPC at 2.5 mg/kg vs. placebo was reduced 33% (medians of 2.0 vs. 3.0, p = 0.180). Time to first SCPC at 5.0 mg/kg vs. placebo was increased 2.9-fold (medians of 4.1 vs. 1.4 months, p = 0.001, Fig. 1) and time to second SCPC was increased 2.0-fold (medians of 10.3 vs. 5.1 months, p = 0.022, Fig. 2). The annual rate of uncomplicated SCPC at 5.0 mg/kg vs. placebo was reduced by 62% (medians of 1.1 vs. 2.9, p = 0.015). ACS events were rare in this study. The annual rate of days hospitalized at 5.0 mg/kg vs. placebo showed a non-significant, 42% reduction (medians of 4.0 vs. 6.9, p = 0.450). Adverse events that occurred in 5% or more of patients in an active dose group and were elevated over placebo by at least 2-fold were arthralgia, pruritus, vomiting, chest pain, diarrhea, road traffic accident, fatigue, myalgia, musculoskeletal chest pain, abdominal pain, influenza and oropharyngeal pain. There were no apparent increases in infections with SelG1 treatment. Five deaths occurred during the study, 2 at 5.0 mg/kg, 1 at 2.5 mg/kg and 2 in placebo; no deaths were deemed related to study drug. Conclusions: The P-selectin inhibitor SelG1 significantly reduced SCPC and appeared to be safe and well tolerated. Significant improvements were also achieved for several secondary endpoints including increases in times to first and second SCPC. Chronic inhibition of P-selectin with once a month IV dosing of SelG1 represents a novel and potentially new disease-modifying, prophylactic treatment option for patients with SCD. clinicaltrials.gov: NCT01895361 Disclosures Kutlar: Novartis Pharmaceuticals: Research Funding. Kanter:Novartis: Consultancy. Rollins:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment. Stocker:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment. Rother:Selexys Pharmaceuticals: Equity Ownership, Other: Previous Employment.
- Published
- 2016
- Full Text
- View/download PDF
10. Expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B cells confers resistance to human complement
- Author
-
Monica Bessler, J Mennone, Russell P. Rother, SA Fidel, A Chodera, Stephen P. Squinto, Scott A. Rollins, and Peter Hillmen
- Subjects
Genetic enhancement ,Immunology ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,CD59 ,Biology ,medicine.disease ,Biochemistry ,Virology ,Molecular biology ,3T3 cells ,Transmembrane protein ,Haematopoiesis ,medicine.anatomical_structure ,Cell culture ,hemic and lymphatic diseases ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Decay-accelerating factor - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder characterized by complement-mediated hemolytic anemia, pancytopenia, and venous thrombosis. These clinical manifestations arise from an underlying molecular defect of bone marrow stem cells. Specifically, somatic mutations in the phosphatidylinositol glycan class A gene result in the ability of blood cells to anchor complement- regulatory proteins (CD59 and DAF) to the cell surface via glycosyl phosphatidylinositol (GPI). In an attempt to circumvent the functional defect in PNH cells, a recombinant transmembrane form of CD59 (CD59-TM) was analyzed for the ability to regulate complement activity. Balb/3T3 stable transfectants expressing similar levels of either CD59-TM or native CD59 (CD59-GPI) were equally protected against human complement- mediated membrane damage. Treatment of these cells with phosphatidylinositol-specific phospholipase C failed to release CD59-TM from the cell surface. Retroviral transduction of GPI-anchoring deficient mouse L cells with CD59-TM resulted in surface expression of the protein and rendered these cells resistant to human complement- mediated membrane damage. Conversely, L cells transduced with CD59-GPI failed to express this protein on the cell surface. A GPI-anchoring deficient complement-sensitive B-cell line derived from a PNH patient was successfully transduced with CD59-TM, resulting in surface expression of the protein. The PNH B cells expressing CD59-TM were protected against classical complement-mediated membrane damage by human serum. Taken together, these data establish that a functional recombinant transmembrane form of CD59 can be expressed on the surface of GPI-anchoring deficient PNH cells and suggest that retroviral gene therapy with this molecule could provide a treatment for PNH patients.
- Published
- 1994
- Full Text
- View/download PDF
11. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria
- Author
-
Anna Gaya, Hubert Schrezenmeier, Robert A. Brodsky, Monica Bessler, Neal S. Young, Antonio M. Risitano, Jaroslaw P. Maciejewski, Russell P. Rother, Luke Coyle, Carlos M. de Castro, Henk André Kroon, Elisabetta Antonioli, Chieh Lin Fu, Peter Hillmen, and Jörg Schubert
- Subjects
Hemolytic anemia ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Anemia ,Immunology ,Hemoglobinuria, Paroxysmal ,Phases of clinical research ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Gastroenterology ,Hemolysis ,Placebos ,Complement inhibitor ,chemistry.chemical_compound ,Internal medicine ,Lactate dehydrogenase ,medicine ,Humans ,Blood Transfusion ,Infusions, Intravenous ,Fatigue ,Aged ,business.industry ,Antibodies, Monoclonal ,Cell Biology ,Hematology ,Eculizumab ,Middle Aged ,medicine.disease ,Surgery ,chemistry ,Area Under Curve ,Paroxysmal nocturnal hemoglobinuria ,Hemoglobinuria ,Female ,Safety ,business ,medicine.drug - Abstract
The terminal complement inhibitor eculizumab was recently shown to be effective and well tolerated in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we extended these observations with results from an open-label, non–placebo-controlled, 52-week, phase 3 clinical safety and efficacy study evaluating eculizumab in a broader PNH patient population. Eculizumab was administered by intravenous infusion at 600 mg every 7 ± 2 days for 4 weeks; 900 mg 7 ± 2 days later; followed by 900 mg every 14 ± 2 days for a total treatment period of 52 weeks. Ninety-seven patients at 33 international sites were enrolled. Patients treated with eculizumab responded with an 87% reduction in hemolysis, as measured by lactate dehydrogenase levels (P < .001). Baseline fatigue scores in the FACIT-Fatigue instrument improved by 12.2 ± 1.1 points (P < .001). Eculizumab treatment led to an improvement in anemia. The increase in hemoglobin level occurred despite a reduction in transfusion requirements from a median of 8.0 units of packed red cells per patient before treatment to 0.0 units per patient during the study (P < .001). Overall, transfusions were reduced 52% from a mean of 12.3 to 5.9 units of packed red cells per patient. Forty-nine patients (51%) achieved transfusion independence for the entire 52-week period. Improvements in hemolysis, fatigue, and transfusion requirements with eculizumab were independent of baseline levels of hemolysis and degree of thrombocytopenia. Quality of life measures were also broadly improved with eculizumab treatment. This study demonstrates that the beneficial effects of eculizumab treatment in patients with PNH are applicable to a broader population of PNH patients than previously studied. This trial is registered at http://clinicaltrials.gov as NCT00130000.
- Published
- 2007
12. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria
- Author
-
Jason Yongsheng Chan, Christopher F. Mojcik, Dupe Elebute, Judith C. Marsh, Russell P. Rother, Peter Hillmen, Stephen J. Richards, and Anita Hill
- Subjects
Hemolytic anemia ,medicine.medical_specialty ,Erythrocytes ,Time Factors ,Immunology ,Hemoglobinuria, Paroxysmal ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Gastroenterology ,Hemolysis ,chemistry.chemical_compound ,Internal medicine ,Lactate dehydrogenase ,medicine ,Humans ,Blood Transfusion ,Complement component 5 ,L-Lactate Dehydrogenase ,business.industry ,Antibodies, Monoclonal ,Complement C5 ,Cell Biology ,Hematology ,Complement System Proteins ,Eculizumab ,medicine.disease ,Complement system ,chemistry ,Paroxysmal nocturnal hemoglobinuria ,Quality of Life ,Hemoglobinuria ,business ,Erythrocyte Transfusion ,medicine.drug - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by clonal expansion of red blood cells (RBCs) lacking the ability to inhibit complement-mediated hemolysis. Eculizumab, a humanized monoclonal antibody that binds the C5 complement protein, blocks serum hemolytic activity. This study evaluated the long-term safety and efficacy of eculizumab in 11 patients with PNH during an open-label extension trial. After completion of an initial 12-week study, all patients chose to participate in the 52-week extension study. Eculizumab, administered at 900 mg every 12 to 14 days, was sufficient to completely and consistently block complement activity in all patients. A dramatic reduction in hemolysis was maintained throughout the study, with a decrease in lactate dehydrogenase (LDH) levels from 3110.7 IU/L before treatment to 622.4 IU/L (P = .002). The proportion of PNH type III RBCs increased from 36.7% at baseline to 58.4% (P = .005). The paroxysm rate of days with gross evidence of hemoglobinuria per patient each month decreased from 3.0 during screening to 0.2 (P < .001) during treatment. The median transfusion rate decreased from 1.8 U per patient each month before eculizumab treatment to 0.3 U per patient each month (P = .001) during treatment. Statistically significant improvements in quality-of-life measures were also maintained during the extension study. Eculizumab continued to be safe and well tolerated, and all patients completed the study. The close relationship between sustained terminal complement inhibition, hemolysis, and symptoms was demonstrated. (Blood. 2005; 106:2559-2565)
- Published
- 2005
13. A novel mechanism of complement-independent clearance of red cells deficient in glycosyl phosphatidylinositol-linked proteins
- Author
-
Monica Bessler, Nico van Rooijen, Panagiotis Pantazopoulos, Wen-Chao Song, Marek Jasinski, Russell P. Rother, and Hector Molina
- Subjects
Anemia, Hemolytic ,Erythrocytes ,Glycosylphosphatidylinositols ,Immunology ,Hemoglobinuria, Paroxysmal ,medicine.disease_cause ,Biochemistry ,Flow cytometry ,Mice ,In vivo ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Mutation ,biology ,medicine.diagnostic_test ,Acquired hemolytic anemia ,Membrane Proteins ,Cell Biology ,Hematology ,Complement System Proteins ,medicine.disease ,Flow Cytometry ,Molecular biology ,In vitro ,Disease Models, Animal ,biology.protein ,Paroxysmal nocturnal hemoglobinuria ,Hemoglobinuria ,Antibody ,Half-Life - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by the increased sensitivity of red blood cells (RBCs) to complement, leading to intravascular hemolysis and hemoglobinuria. PNH is due to the expansion of a cell clone that has acquired a mutation in the PIGA gene. Mice with targeted Piga gene inactivation genetically mimic the human disease and have phosphatidylinositol glycan class A-negative (PIGA-) RBCs with a reduced half-life in circulation. Although PIGA-RBCs are hypersensitive to complement in vitro, their complement sensitivity in vivo is barely detectable. Here we show that the shortened survival of PIGA- RBCs is independent of complement either by using inhibitory C5 antibodies or by transfusion into C5-, C4-, C3-, or factor B-deficient mice. Splenectomy or high-dose cortisone treatment had no effect on the shorter survival of PIGA- RBCs. However, treatment with liposome-encapsulated clodronate, an agent that depletes macrophages in vivo, normalized the half-life of PIGA- RBCs. This indicates that the shortened survival of PIGA- RBCs is due to a novel pathway of PIGA- RBC clearance that is mediated by macrophages, but occurs independently of complement. Future investigations will show whether this novel pathway of PIGA- RBC destruction identified in mice may also operate in patients with PNH. (Blood. 2004;103:2827-2834)
- Published
- 2003
14. Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease
- Author
-
Thomas Philipp, Russell P. Rother, Ulrich Dührsen, Alexander Röth, and Andreas Hüttmann
- Subjects
Hemagglutination ,biology ,Cold agglutinin disease ,Anemia ,business.industry ,Immunology ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Virology ,Complement system ,Complement inhibitor ,Immunoglobulin M ,hemic and lymphatic diseases ,medicine ,biology.protein ,Hemoglobinuria ,business ,medicine.drug - Abstract
To the editor: Cold agglutinin disease (CAD) is characterized by immunoglobulin M (IgM)–mediated hemagglutination and robust complement activation leading to intravascular hemolysis and hemolysis-related symptoms including anemia, fatigue, dyspnea, hemoglobinuria, and acrocyanosis.[1][1][⇓][2
- Published
- 2009
- Full Text
- View/download PDF
15. Placebo-Controlled, Double-Blind, First-In-Human, Ascending Single Dose and Multiple Dose, Healthy Subject Study Of Intravenous-Administered SelG1, a Humanized Anti-P-Selectin Antibody In Development For Sickle Cell Disease
- Author
-
Stocker, Jonathan W., primary, Mandarino, Debra, additional, Kawar, Ziad, additional, Alvarez, Richard, additional, Falconer, David, additional, Rollins, Scott A., additional, and Rother, Russell P., additional
- Published
- 2013
- Full Text
- View/download PDF
16. Placebo-Controlled, Double-Blind, First-In-Human, Ascending Single Dose and Multiple Dose, Healthy Subject Study Of Intravenous-Administered SelG1, a Humanized Anti-P-Selectin Antibody In Development For Sickle Cell Disease
- Author
-
Jonathan W. Stocker, Debra Mandarino, Ziad Kawar, Richard Alvarez, David Falconer, Scott A. Rollins, and Russell P. Rother
- Subjects
medicine.medical_specialty ,Hematology ,Dose ,business.industry ,Immunology ,Cmax ,Cell Biology ,Placebo ,Biochemistry ,Gastroenterology ,Surgery ,Pharmacokinetics ,Internal medicine ,Pharmacodynamics ,Cohort ,medicine ,business ,Adverse effect - Abstract
SelG1 is a humanized anti-P-selectin monoclonal antibody being developed as a treatment for sickle cell disease (SCD). Extensive data have been published that suggest a pivotal role for P-selectin in the pathophysiology of SCD. Much of this work has been conducted in mice engineered to express human β hemoglobin S (sickle cell hemoglobin). These mice have a remarkably similar disease pathology to that observed in human SCD including vasoocclusion. Using these mice, investigators have demonstrated P-selectin interactions between the endothelium and sickled red blood cells, leukocytes and platelets. Additional studies have demonstrated direct P-selectin mediated binding of leukocytes with platelets. All of these cell-cell interactions have been implicated in SCD vasoocclusion. Further, blockade or genetic absence of P-selectin decreases or eliminates these cell-cell interactions and vasoocclusion. A Phase I clinical study was conducted to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SelG1. This was a single-center, double-blind, placebo-controlled, first-in-human, ascending single dose and multiple dose study of intravenous (IV)-administered SelG1 in healthy adult male and female subjects. There were 5 dosing cohorts in the study (A through E): Ascending single dose cohorts: Cohort A:0.2 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort B:0.5 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort C:1.0 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort D:5.0 mg/kg IV dose of SelG1 (n=6) or placebo (n=2). Multi-dose cohort: Cohort E:two 8.0 mg/kg IV doses of SelG1 (n=5) or placebo (n=2); the doses were given 2 weeks apart. In Cohorts A through D, SelG1 was slowly eliminated (mean t1/2 = 75.6 to 500 hours). Mean t1/2 values increased in a dose dependent manner. The exposure to SelG1 (mean Cmax, AUC0-t, and AUC0-∞) increased in a greater than proportional manner over the dose range. In Cohort E, SelG1 was slowly eliminated (mean t1/2 = 363 hours for the second infusion). The mean Cmax and AUC0-336values were 1.6- and 1.7-fold higher, respectively, after the second infusion relative to the first infusion. The PD data demonstrate that P-selectin function was completely blocked for a minimum of 28 days in Cohort D and at least 56 days in Cohort E. Twenty-six of the 27 subjects who received study drug completed the study, with 1 placebo subject in Cohort D withdrawing himself from the study due to the required travel commitment. There were no deaths, serious adverse events, or severe AEs reported in any subject. There were no increases in the number or severity of AEs with increasing dosages or with multi-dose administration. The percentage of subjects experiencing an AE was similar between the SelG1-treated subjects and the placebo-treated subjects; in Cohorts A-D, 66.7% of SelG1-treated subjects and 60.0% of placebo subjects reported at least 1 AE, while in Cohort E, 60.0% of SelG1-treated subjects and 50.0% of placebo-treated subjects reported at least 1 AE. Only 1 AE occurred in more than 1 subject; vessel puncture site hematoma occurred in 1 subject of Cohort A, 1 subject of Cohort C, and 2 subjects of Cohort E. All other AEs occurred in only 1 subject and were mild to moderate in severity. No AEs in any subject were deemed “related” to study drug. No clinically significant findings were noted from vital sign measurements, physical examinations, or 12-lead ECGs for this study. No biochemistry, hematology, or other laboratory data were reported as clinically significant or were reported as AEs; there were no trends that indicated increases or decreases in mean or median values over time, and there were no dose-dependent increases or decreases in mean or median values. There were no demonstrable changes in coagulation parameters or increased bleeding tendencies. No specific antibody response to SelG1 occurred in any of the subjects. In summary, the administration of SelG1 was well tolerated in this group of healthy male and female subjects. A Phase II clinical study to evaluate the clinical efficacy of SelG1 in SCD patients is currently underway. Disclosures: Stocker: Selexys Pharmaceuticals: Employment, Equity Ownership. Mandarino:Selexys Pharmaceuticals: CRO Other. Kawar:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Alvarez:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Falconer:Selexys Pharmaceuticals: Employment, Equity Ownership. Rollins:Selexys Pharmaceuticals: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Rother:Selexys Pharmaceuticals: Employment, Equity Ownership.
- Published
- 2013
- Full Text
- View/download PDF
17. Expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B cells confers resistance to human complement
- Author
-
R P, Rother, S A, Rollins, J, Mennone, A, Chodera, S A, Fidel, M, Bessler, P, Hillmen, and S P, Squinto
- Subjects
B-Lymphocytes ,Herpesvirus 4, Human ,Mice, Inbred BALB C ,Membrane Glycoproteins ,Base Sequence ,Glycosylphosphatidylinositols ,Molecular Sequence Data ,Gene Transfer Techniques ,Hemoglobinuria, Paroxysmal ,Gene Expression ,CD59 Antigens ,3T3 Cells ,Complement System Proteins ,Recombinant Proteins ,Cell Line ,Mice ,L Cells ,Antigens, CD ,Animals ,Humans ,Cell Line, Transformed - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder characterized by complement-mediated hemolytic anemia, pancytopenia, and venous thrombosis. These clinical manifestations arise from an underlying molecular defect of bone marrow stem cells. Specifically, somatic mutations in the phosphatidylinositol glycan class A gene result in the ability of blood cells to anchor complement-regulatory proteins (CD59 and DAF) to the cell surface via glycosyl phosphatidylinositol (GPI). In an attempt to circumvent the functional defect in PNH cells, a recombinant transmembrane form of CD59 (CD59-TM) was analyzed for the ability to regulate complement activity. Balb/3T3 stable transfectants expressing similar levels of either CD59-TM or native CD59 (CD59-GPI) were equally protected against human complement-mediated membrane damage. Treatment of these cells with phosphatidylinositol-specific phospholipase C failed to release CD59-TM from the cell surface. Retroviral transduction of GPI-anchoring deficient mouse L cells with CD59-TM resulted in surface expression of the protein and rendered these cells resistant to human complement-mediated membrane damage. Conversely, L cells transduced with CD59-GPI failed to express this protein on the cell surface. A GPI-anchoring deficient complement-sensitive B-cell line derived from a PNH patient was successfully transduced with CD59-TM, resulting in surface expression of the protein. The PNH B cells expressing CD59-TM were protected against classical complement-mediated membrane damage by human serum. Taken together, these data establish that a functional recombinant transmembrane form of CD59 can be expressed on the surface of GPI-anchoring deficient PNH cells and suggest that retroviral gene therapy with this molecule could provide a treatment for PNH patients.
- Published
- 1994
18. Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease
- Author
-
Röth, Alexander, primary, Hüttmann, Andreas, additional, Rother, Russell P., additional, Dührsen, Ulrich, additional, and Philipp, Thomas, additional
- Published
- 2009
- Full Text
- View/download PDF
19. Successful Pregnancy Outcomes in Paroxysmal Nocturnal Hemoglobinuria with Long-Term Eculizumab Treatment
- Author
-
Kelly, Richard, primary, Arnold, Louise, primary, Richards, Stephen J., primary, Hill, Anita, primary, Bomken, Charlotte, primary, Hanley, John, primary, Loughney, Andrew, primary, Khursigara, Gus, primary, Rother, Russell P., primary, Chalmers, Elizabeth, primary, Fitzsimons, Edward, primary, Nakamura, Ryotaro, primary, Gaya, Anna, primary, Rotoli, Bruno, primary, Risitano, Antonio M., primary, Schubert, Joerg, primary, and Hillmen, Peter, primary
- Published
- 2008
- Full Text
- View/download PDF
20. Eculizumab Reduces Pulmonary Hypertension through Inhibition of Hemolysis-Associated Nitric Oxide Consumption in Patients with Paroxysmal Nocturnal Hemoglobinuria
- Author
-
Hill, Anita, primary, Rother, Russell P., primary, Wang, Xunde, primary, Sapsford, Robert J, primary, Collinson, Paul O, primary, Gaze, David C, primary, Morris, Sidney M, primary, Scally, Andrew, primary, Quinn-Senger, Kerry, primary, Richards, Stephen J, primary, Bessler, Monica, primary, Kelly, Richard, primary, Hillmen, Peter, primary, and Gladwin, Mark, primary
- Published
- 2008
- Full Text
- View/download PDF
21. Modification of the Eculizumab Dose to Successfully Manage Intravascular Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria.
- Author
-
Kelly, Richard, primary, Arnold, Louise, additional, Richards, Stephen, additional, Hill, Anita, additional, vanBijnen, Sandra, additional, Muus, Petra, additional, Dorr, Donna, additional, Brodsky, Robert, additional, Khursigara, Gus, additional, Rother, Russell P., additional, and Hillmen, Peter, additional
- Published
- 2008
- Full Text
- View/download PDF
22. Successful Treatment of Atypical Hemolytic Uremic Syndrome with the Complement Inhibitor Eculizumab.
- Author
-
Nuernberger, Jens, primary, Witzke, Oliver, primary, Rother, Russell P., primary, Philipp, Thomas, primary, Vester, Udo, primary, Baba, Hideo, primary, Zimmerhackl, Lothar Bernd, primary, and Kribben, Andreas, primary
- Published
- 2008
- Full Text
- View/download PDF
23. Prevention of Graft-Versus-Host Disease in Mouse Model Using Anti-Mouse C5 Antibody.
- Author
-
Nishimura, Jun-ichi, primary, DeOliveira, Divino, additional, Chen, Benny J., additional, Kanakura, Yuzuru, additional, Rother, Russell P., additional, and Chao, Nelson J., additional
- Published
- 2007
- Full Text
- View/download PDF
24. High Incidence of Progression to Chronic Renal Insufficiency in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).
- Author
-
Hillmen, Peter, primary, Elebute, Modupe O., primary, Kelly, Richard, primary, Urbano-Ispizua, Alvaro, primary, Rother, Russell P., primary, Fu, Chieh-Lin, primary, and Browne, Paul, primary
- Published
- 2007
- Full Text
- View/download PDF
25. Sustained Improvements in Transfusion Requirements, Fatigue and Thrombosis with Eculizumab Treatment in Paroxysmal Nocturnal Hemoglobinuria.
- Author
-
Socié, Gerard, primary, Hillmen, Peter, primary, Muus, Petra, primary, Schubert, Jörg, primary, Dührsen, Ulrich, primary, Risitano, Antonio M., primary, Rother, Russell P., primary, Brodsky, Robert A., primary, and Szer, Jeffrey, primary
- Published
- 2007
- Full Text
- View/download PDF
26. Successful Treatment of Atypical Hemolytic Uremic Syndrome with the Complement Inhibitor Eculizumab
- Author
-
Udo Vester, Jens Nuernberger, Oliver Witzke, Thomas Philipp, Russell P. Rother, Lothar Bernd Zimmerhackl, Andreas Kribben, and Hideo A. Baba
- Subjects
medicine.medical_specialty ,Thrombotic microangiopathy ,business.industry ,Immunology ,Cell Biology ,Hematology ,Microangiopathic hemolytic anemia ,Eculizumab ,urologic and male genital diseases ,medicine.disease ,Biochemistry ,Gastroenterology ,Transplantation ,Complement inhibitor ,Factor H ,Internal medicine ,Atypical hemolytic uremic syndrome ,medicine ,Paroxysmal nocturnal hemoglobinuria ,business ,medicine.drug - Abstract
Background: Atypical hemolytic uremic syndrome (aHUS) is a rare microangiopathic hemolytic anemia characterized by the uncontrolled progression of the alternative complement pathway due to genetic or acquired dysregulation of steady state alternative pathway activity leading to a proinflammatory and prothrombotic condition. Atypical HUS is characterized by intravascular hemolysis, consumptive thrombocytopenia, and microvascular glomerular thrombosis with the formation of thrombi in glomerular capillaries. As the thrombotic microangiopathy is particularly severe in the renal microvasculature, the disease inevitably leads to acute kidney injury with most cases progressing to end-stage-renal-disease. Eculizumab is a complement inhibitor that has been shown to completely and consistently block the activation of the terminal complement cascade thereby preventing the generation of the proinflammatory and prothrombotic molecules C5a and C5b-9. In recent phase 3 clinical studies in patients with the rare hemolytic disease paroxysmal nocturnal hemoglobinuria, chronic eculizumab treatment was shown to be safe, and demonstrated an effective reduction in intravascular hemolysis and a 85% reduction in thrombotic events. Aim: The safety and efficacy of eculizumab in the management of aHUS. We sought to investigate the potential benefit of the complement inhibitor eculizumab in aHUS, a disease characterized by uncontrolled progression of the alternative complement pathway. Methods: Two aHUS patients that were unresponsive to plasmapheresis were dosed with 600 mg of eculizumab to inhibit the terminal complement cascade. The patients were monitored closely for adverse events and platelet counts, creatinine and haptoglobin were assessed. PK/PD analyses were performed on one of the two patients. Results: We report aHUS in two patients successfully treated with the complement inhibitor eculizumab. The first was a 37-year old female with recurrence of aHUS after renal transplantation. At the age of 25 years, the patient developed aHUS with end-stage-renal- disease and stayed on dialysis until she received a first cadaveric kidney transplant 5 years later. This first transplant was lost 5 weeks after transplantation due to chronic aHUS. A second attempt of kidney transplantation was undertaken using a calcineurin-inhibitor free immunosuppressive protocol and despite immediate plasmapheresis (4 times), aHUS worsened (platelet count dropping, haptoglobin decreasing, creatinine increasing) indicating a high probability of repeated renal transplant loss. The patient was characterized as having a missense mutation in the gene encoding the complement regulatory protein factor H. The current literature indicates that patients with such mutations have a high incidence of graft rejection (7 of 8 grafts rejected). Eculizumab was therefore administered and resulted in immediate and complete inhibition of terminal complement activation for at least 5 days. During the week following treatment, platelet count increased, hemolysis normalized (as assessed by haptoglobin levels), and transplant function recovered (as assessed by creatinine levels) indicating successful reversal of aHUS (see Figure A). The second patient was an 18-year old female with first the initial manifestation of aHUS. After a total of 18 plasmaphereses, the young patient was referred to our hospital with aHUS. When symptoms persisted despite another three plasmaphereses in our University hospital, we decided to administer eculizumab. Over the following week, platelet count normalized, hemolysis was reversed, and renal function partially recovered (see Figure B). Summary: This is the first report evaluating the use of a complement inhibitor as a potential therapy for the treatment of aHUS. These data suggest that eculizumab therapy results in a reduction in thrombotic microangiopathy and hemolysis as evidenced by a reversal of thrombocytopenia, the normalization of hemolytic parameters, and the recovery of kidney transplant function. These data suggest the eculizumab modifies the course of aHUS and warrant further clinical investigation to confirm whether complement inhibition with eculizumab is an effective treatment of this devastating and life-threatening disease. Figure Figure
- Published
- 2008
- Full Text
- View/download PDF
27. Eculizumab Reduces Pulmonary Hypertension through Inhibition of Hemolysis-Associated Nitric Oxide Consumption in Patients with Paroxysmal Nocturnal Hemoglobinuria
- Author
-
David Gaze, Mark T. Gladwin, Andrew J. Scally, Monica Bessler, Paul O. Collinson, Robert J. Sapsford, Peter Hillmen, Anita Hill, Stephen J. Richards, Richard Kelly, Sidney M. Morris, Russell P. Rother, Kerry Quinn-Senger, and Xunde Wang
- Subjects
Hemolytic anemia ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Pulmonary hypertension ,Gastroenterology ,chemistry.chemical_compound ,Complement inhibitor ,chemistry ,Lactate dehydrogenase ,Internal medicine ,Paroxysmal nocturnal hemoglobinuria ,medicine ,Hemoglobinemia ,Hemoglobin ,business ,medicine.drug - Abstract
The depletion of nitric oxide (NO) by cell-free plasma hemoglobin and arginase during intravascular hemolysis has been implicated in the dysregulation of vasomotor tone and the enhancement of procoagulant and prothrombotic activities. Pulmonary hypertension (PHT), an emerging common complication of hereditary hemolytic anemias, has been mechanistically and epidemiologically linked to intravascular hemolysis and NO depletion. Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by chronic and brisk hemolysis, as well as elevated cell-free plasma hemoglobin. We have previously reported that approximately 50% of PNH patients have PHT as measured by doppler echocardiograpy. Further, the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been generally demonstrated to be a sensitive and specific measure of right-sided cardiac stress due to PHT and has more recently been shown to be a strong predictor of pulmonary hypertension (PHT) and mortality in patients with hemolytic anemias (defined as NT-proBNP ≥ 160 pg/ml). Eculizumab, a terminal complement inhibitor, has been demonstrated to significantly and rapidly reduce hemolysis, thereby providing beneficial effects on regulation of smooth muscle tone and thrombosis in patients with PNH. To evaluate the efficacy of eculizumab in the regulation of cell-free plasma hemoglobin levels, nitric oxide depletion, and subsequent cardiovascular morbidities in patients with PNH. Levels of hemoglobinemia, arginase and nitric oxide depletion were assessed in 73 evaluable eculizumab- and placebo-treated PNH in the phase III randomized, placebo-controlled trial (TRIUMPH). In addition, levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were assessed as a measure of PHT, and systolic and diastolic systemic arterial pressures were examined in eculizumab- and placebo-treated patients. At baseline, levels of lactate dehydrogenase (LDH), cell-free plasma hemoglobin, arginase 1 and arginase 1 enzyme activity were highly elevated compared to normal values. Levels of hemolysis and NO consumption were shown to be much greater in PNH (more than 6- and 10-fold, respectively) than in patients with other hemolytic diseases. There were substantial correlations between cell-free plasma hemoglobin levels and both LDH (R = 0.5094) and plasma consumption of nitric oxide (NO) (R = 0.9529). Strong correlations between arginase 1 and both cell-free plasma hemoglobin (R = 0.9367) and arginase 1 enzyme activity (R = 0.9081) were also demonstrated. Following eculizumab therapy, measures of hemolysis were significantly reduced from baseline, including LDH (2200 ± 158 to 327 ± 68 U/L) and cell-free plasma hemoglobin (98.8 ± 23.24 to 15.2 ± 5.05 mg/dL), while levels in placebo-treated patients remained unchanged; a concomitant reduction in NO consumption was also observed (see Figure). In addition, at baseline, 46.6% (34/73) of PNH patients in the TRIUMPH study had levels of NT-proBNP ≥ 160 pg/ml, indicating PHT in these patients. Eculizumab-treated patients showed a 50% reduction in the incidence of PHT over the course of the 26-week treatment period from 52.5% to 26.3%, while PHT did not change with placebo (39.4% to 43.8%; P Figure. Effect of eculizumab on cell-free plasma hemoglobin and NO consumption Figure. Effect of eculizumab on cell-free plasma hemoglobin and NO consumption
- Published
- 2008
- Full Text
- View/download PDF
28. Modification of the Eculizumab Dose to Successfully Manage Intravascular Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria
- Author
-
Petra Muus, Donna Dorr, Stephen J. Richards, Louise Arnold, Gus Khursigara, Peter Hillmen, Anita Hill, Sandra vanBijnen, Richard Kelly, Robert A. Brodsky, and Russell P. Rother
- Subjects
medicine.medical_specialty ,Maintenance dose ,business.industry ,Immunology ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Hemolysis ,Surgery ,Complement inhibitor ,Regimen ,Anesthesia ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Hemoglobinuria ,Dosing ,business ,medicine.drug - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by a lack of the terminal complement inhibitor CD59 on erythrocytes that renders these cells susceptible to chronic hemolysis. Eculizumab blocks terminal complement resulting in reductions in hemolysis, thrombotic events, renal impairment and transfusion requirement, as well as improvement in quality of life. The standard dosing regimen for eculizumab is 600 mg/week for 4 weeks (induction); 900 mg one week later; and then 900 mg every 14 ± 2 days (maintenance). This regimen maintains eculizumab levels >35 μg/mL, which is sufficient to completely and consistently block complement-mediated hemolysis in patients with PNH. In PNH clinical trials, 900 mg of eculizumab every 14 ± 2 days effectively and consistently blocked complement-mediated hemolysis in 98% of patients (n=195). During the studies, 10–15% of patients experienced an increase in hemolysis (elevation of LDH) near the end of the 14-day dosing interval with a return of pre-eculizumab symptoms such as hemoglobinuria, dysphagia, abdominal pain, or fatigue. The dosing interval was reduced to 12 days, as specified by label, resulting in sustained complement blockade, control of hemolysis and resolution of symptoms in nearly all patients. Three of the original 195 patients (2%) were not consistently blocked with the approved dosing regimen. Alternative eculizumab dosing regimens were investigated in these patients to assess their effectiveness and safety. Two different dosing regimens were employed; both included a maintenance phase with 1200 mg every 14 days. One regimen also included an induction period of 900 mg weekly for 5 doses. LDH, pharmacokinetics (PK), and clinical signs of complement breakthrough were monitored. The time from first eculizumab treatment to initial breakthrough on the 900 mg every 14 days ranged from 2 to 19 mo., and the reduction in the dosing interval to 900 mg every 12 days, as specified in the label, did not adequately control hemolysis in each of these 4 patients. Patient 1 was managed for 6 mo. with 900 mg every 12 days before experiencing additional complement breakthrough episodes (Figure, panel A). LDH levels (closed diamonds) reached 9234 U/L (ULN, 430-450 U/L) and breakthrough symptoms occurred 2 days prior to the next dose. The patient was re-induced with 900 mg eculizumab every 7 days for 5 weeks followed by 1200 mg every 14 days. Trough levels of eculizumab increased (open circles) each week during the induction phase (42.7 – 81.8 μg/ml) resulting in an immediate reduction in LDH to near normal levels. A maintenance dose of 1200 mg every 14 days in this patient resulted in sustained complement blockade. Patient 2 experienced breakthrough hemolysis after 19 mo. of standard dosing. Complement breakthrough occurred during a post-cholecystectomy infective endocarditis. After an adjustment to 900 mg every 12 days did not control complement breakthrough (Figure, panel B), the dose was changed to 1200 mg every 14 days without re-induction. This regimen resulted in sufficient levels of eculizumab to consistently reduce hemolysis to near normal levels. Further episodes of hemoglobinuria and other symptoms of hemolysis were not observed. Two additional patients received 1200 mg every 14 days without re-induction, one following complement breakthrough on the approved dose and the other due to the convenience of the 14 day interval with the 1200 mg dose. Complete complement blockade has been maintained in these patients for 8 mo. and 12 mo. to date, respectively. After 1 year of sustained complement blockade with the 1200 mg maintenance dose, patient 1 again demonstrated a breakthrough. Complement inhibition is now being maintained in this patient by a 1200 mg dose every 14 days with an additional 1200 mg dose in between the 14 day dosing interval every 4–5 doses. There were no reported adverse events in any of the four patients in which the 1200 mg dosing regimens were administered. In summary, these data demonstrate good correlation between eculizumab and LDH levels, suggesting that a breakthrough in complement activity due to insufficient drug levels can be monitored by levels of LDH near the end of the dosing interval. These results illustrate that two alternative-dosing regimens are well tolerated and can be effectively employed in the small percentage of PNH patients in which complement inhibition is not consistently maintained using the standard dose. Figure Figure
- Published
- 2008
- Full Text
- View/download PDF
29. Successful Pregnancy Outcomes in Paroxysmal Nocturnal Hemoglobinuria with Long-Term Eculizumab Treatment
- Author
-
Louise Arnold, Anita Hill, Antonio M. Risitano, John Hanley, Gus Khursigara, Russell P. Rother, Elizabeth Chalmers, Joerg Schubert, Charlotte Bomken, Anna Gaya, Andrew D. Loughney, Peter Hillmen, Richard Kelly, Ryotaro Nakamura, Bruno Rotoli, Edward J. Fitzsimons, and Stephen J. Richards
- Subjects
medicine.medical_specialty ,Pregnancy ,business.industry ,Postpartum Complication ,Immunology ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Complement inhibitor ,Internal medicine ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Gestation ,Hemoglobinuria ,business ,Postpartum period ,medicine.drug - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by a lack of the terminal complement inhibitor CD59 on erythrocytes that renders these cells susceptible to chronic hemolysis resulting in anemia, fatigue, abdominal pain, kidney dysfunction, pulmonary hypertension, and life-threatening thromboembolism (TE). During pregnancy, hemolysis frequently worsens and the incidence of TE increases, posing a high risk of both fetal and maternal mortality. Eculizumab is a terminal complement inhibitor that reduces hemolysis, transfusion requirements, and TE while improving fatigue and quality of life in patients with PNH. Eculizumab contains a hybrid constant region with components of both IgG2 and IgG4. Whether eculizumab crosses the placenta is not known. The eculizumab clinical trial protocols specified withdrawal of patients who became pregnant during the study. There were 5 reported pregnancies during the PNH clinical trials (n=195) prior to withdrawal from the study. To evaluate the safety and efficacy of eculizumab in the management of PNH during pregnancy, we reviewed the physician-reported adverse events (AEs), PK/PD, and distribution of eculizumab, duration of drug exposure during gestation, complications during and after pregnancy, and general health of the newborn in patients with PNH who became pregnant during the eculizumab clinical trials. Of the 5 reported pregnancies, one patient elected termination and 3 patients withdrew from eculizumab therapy between 4 to 16 weeks of gestation and continued pregnancy through term. There were no apparent complications or AEs related to drug and all 3 patients delivered healthy newborns. One patient was treated with low molecular weight heparin (LMWH) from the time she discontinued eculizumab to three months after delivery. She developed hyperpyrexia and was diagnosed with fever of unknown origin shortly after delivery. She was treated and then discharged. There have been no reported postpartum complications in any of these deliveries to date. The fifth patient withdrew from the study but continued on eculizumab treatment throughout the whole pregnancy and post-partum. She initiated eculizumab treatment in 2002 reducing her LDH from 10,300U/L to 490 U/L (normal range 150 to 480 U/L). Her transfusion requirement reduced from 4 units every 6 weeks to 2 units per year in order to maintain her hemoglobin above 8 g/dl. She was commenced on LMWH at week 8 of gestation and she remained on it for the duration of her pregnancy and postpartum. During pregnancy, she was transfused more frequently to maintain her hemoglobin above 9 g/dl. At week 28 of gestation, she experienced an episode of hemoglobinuria and abdominal pain for 3–4 days prior to her next dose of eculizumab and therefore the dosing interval was adjusted from 14 to 12 days (11 days to avoid weekends) as per the approved 900mg dose. She had no further episodes of breakthrough and her LDH levels were maintained below 450 U/L. The patient was induced at term and delivered a healthy newborn. On the day of delivery, there was no detectable eculizumab in the cord blood (see table). At day 1 and 9 postpartum, there was no detectable eculizumab in breast milk samples. To date, the patient shows no clinical signs of thrombosis or other morbidities typically associated with PNH. The first evaluation of eculizumab treatment from conception to delivery in a patient with PNH treated with eculizumab demonstrated that the drug was tolerated and the pregnancy was successful. There was no evidence of thromboses or other morbidities during the postpartum period. There have been no reported events of congenital anomaly/birth defects in the offspring of any patient with PNH who became pregnant during participation in our clinical studies. Further, there are currently two patients being followed who received eculizumab treatment either during the last trimester (started eculizumab at week 26) or throughout gestation to term. Pregnancy in PNH is associated with an extremely high maternal risk. A review of the 5 clinical trial cases demonstrated that patients receiving eculizumab during pregnancy had no obvious complications through the post-partum period and that a slightly higher dose of eculizumab may be required during pregnancy than in non-pregnant patients with PNH. In addition, eculizumab does not appear to cross the placenta or to be secreted into breast milk. Eculizumab therapy may play a significant role in the management of pregnancy in patients with PNH. Table. Eculizumab levels at delivery | Eculizumab Levels (μg/ml)* | Post Partum | |:------------------------------------------------------------------------------------------------:| ----------- | ---- | | | Day 0 | Day1 | Day 9** | | NM. Not Measured | | *, a level of 35 μg/ml or more has been shown to completely block terminal complement activation | | **An additional dose was given between Day 1 and Day 9 | | Eculizumab serum levels in mother | 116.1 | 81.3 | 146 | | Eculizumab serum levels in cord blood | | NM | NM | | Eculizumab in breast milk | | |
- Published
- 2008
- Full Text
- View/download PDF
30. The Terminal Complement Inhibitor Eculizumab Reduces Thrombosis in Patients with Paroxysmal Nocturnal Hemoglobinuria.
- Author
-
Hillmen, Peter, primary, Muus, Petra, primary, Dührsen, Ulrich, primary, Risitano, Antonio M., primary, Schubert, Jörg, primary, Young, Neal S., primary, Schrezenmeier, Hubert, primary, Szer, Jeffrey, primary, Brodsky, Robert A., primary, Hill, Anita, primary, Socié, Gérard, primary, Rollins, Scott A., primary, Rother, Russell P., primary, Bell, Leonard, primary, and Luzzatto, Lucio, primary
- Published
- 2006
- Full Text
- View/download PDF
31. Treatment with the Terminal Complement Inhibitor Eculizumab Improves Anemia in Patients with Paroxysmal Nocturnal Hemoglobinuria: Phase III Triumph Study Results.
- Author
-
Schubert, Jörg, primary, Hillmen, Peter, primary, Dührsen, Ulrich, primary, Young, Neal S., primary, Elebute, Modupe, primary, Szer, Jeffrey, primary, Gianfaldoni, Giacomo, primary, Socié, Gérard, primary, Browne, Paul, primary, Mojcik, Christopher F., primary, Rother, Russell P., primary, and Muus, Petra, primary
- Published
- 2006
- Full Text
- View/download PDF
32. High Definition Contrast-Enhanced MR Imaging in Paroxysmal Nocturnal Hemoglobinuria (PNH) Suggests a High Frequency of Subclinical Thrombosis.
- Author
-
Hill, Anita, primary, Reid, Scott A., primary, Rother, Russell P., primary, Gladwin, Mark T., primary, Collinson, Paul O., primary, Gaze, David C., primary, Lowe, Angela, primary, Guthrie, Ashley, primary, Sivananthan, Mohan U., primary, and Hillmen, Peter, primary
- Published
- 2006
- Full Text
- View/download PDF
33. Blockade of Intravascular Hemolysis in PNH with the Terminal Complement Inhibitor Eculizumab Unmasks Low-Level Hemolysis Potentially Occurring through C3 Opsonization.
- Author
-
Hill, Anita, primary, Rother, Russell P., primary, Risitano, Antonio M., primary, Cole, Duncan S., primary, Cullen, Matthew J., primary, Richards, Stephen J., primary, Selleri, Carmine, primary, Ricci, Patrizia, primary, Rotoli, Bruno, primary, Luzzatto, Lucio, primary, and Hillmen, Peter, primary
- Published
- 2006
- Full Text
- View/download PDF
34. Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Interim Shepherd Phase III Clinical Study.
- Author
-
Young, Neal S., primary, Antonioli, Elisabetta, primary, Rotoli, Bruno, primary, Schrezenmeier, Hubert, primary, Schubert, Jörg, primary, Urbano-Ispizua, Alvaro, primary, Coyle, Luke, primary, de Castro, Carlos, primary, Fu, Chieh-Lin, primary, Maciejewski, Jaroslaw P., primary, Mojcik, Christopher F., primary, Rother, Russell P., primary, and Hillmen, Peter, primary
- Published
- 2006
- Full Text
- View/download PDF
35. Nitric Oxide Consumption and Pulmonary Hypertension in Patients with Paroxysmal Nocturnal Hemoglobinuria.
- Author
-
Hill, Anita, primary, Wang, Xunde, primary, Sapsford, Robert J., primary, Russell, Rother P., primary, Farrell, Alison L., primary, Jessop, Hilary A., primary, McGawley, Gina M., primary, Oxborough, David L., primary, Pleasants, Paul, primary, Richards, Stephen J., primary, Arnold, Louise M., primary, Buchanan, David M., primary, Rollinson, Sara, primary, Gladwin, Mark T., primary, and Hillmen, Peter, primary
- Published
- 2005
- Full Text
- View/download PDF
36. The Effect of Eculizumab Therapy on Red Cell Response Kinetics in Patients with Paroxysmal Nocturnal Hemoglobinuria.
- Author
-
Richards, Stephen J., primary, Cullen, Matthew J., primary, Dickinson, Anita J., primary, Hill, Anita, primary, Buchanon, David, primary, Arnold, Louise, primary, Elebute, Modupe, primary, Rother, Russell P., primary, and Hillmen, Peter, primary
- Published
- 2005
- Full Text
- View/download PDF
37. High Incidence of Progression to Chronic Renal Insufficiency in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Author
-
Modupe O. Elebute, Chieh-Lin Fu, Richard Kelly, Alvaro Urbano-Ispizua, Paul Browne, Russell P. Rother, and Peter Hillmen
- Subjects
endocrine system ,Pediatrics ,medicine.medical_specialty ,business.industry ,Anemia ,medicine.medical_treatment ,Incidence (epidemiology) ,Immunology ,Renal function ,Cell Biology ,Hematology ,Hemosiderosis ,Eculizumab ,medicine.disease ,Biochemistry ,Thrombosis ,Gastroenterology ,Internal medicine ,Paroxysmal nocturnal hemoglobinuria ,medicine ,business ,Dialysis ,medicine.drug - Abstract
PNH is a debilitating and life-threatening clonal hematopoietic disease in which lysis of PNH RBCs manifests with chronic hemolysis, anemia and thrombosis. Incidence of progression to chronic renal insufficiency (CRI; GFR < 60 ml/min/1.73 m2) has not been previously examined in a controlled trial. Renal damage in PNH has been associated with chronic hemolysis and subsequent hemosiderosis and/or microvascular thrombosis. A previous study showed that 9/9 hemolytic PNH patients had renal hemosiderin by MRI [Hill et al., 48th Annual ASH meeting, Dec. 9, 2006]. All patients entering into the recently completed eculizumab multinational studies in hemolytic PNH patients (Phase 2, TRIUMPH, SHEPHERD; n=195) were screened for CRI and for a previous clinical diagnosis of CRI and acute renal failure (ARF). The median GFR was 81 ml/min/1.73 m2 (63–97). The incidence of CRI at screening was 21% (40/195) with 10/40 patients having severe CRI (GFR ≤30ml/min). Of 195 patients, 7% (14/195) had previously experienced episodes of ARF which showed at least partial recovery and 21% (3/14) of these patients subsequently developed CRI. Only 25% (10/40) of patients with pre-study CRI had been clinically diagnosed with CRI. Most patients (68%, 27/40) who developed CRI had not previously been clinically diagnosed with either ARF or CRI. Median disease duration and median time from first thrombosis to study entry were increased in CRI patients vs non-CRI patients (8.8 yrs vs 5.1 yrs and 4.6 yrs vs 3.2 yrs, respectively). Proportions of patients with PNH for 10 or more years and 10 or more years since first thrombosis were increased in CRI patients vs non-CRI patients (48%, 19/40 vs 28%, 43/155, P=.02; and 13%, 5/40 vs 3%, 5/155, P=.03, respectively). Eculizumab was safe and well-tolerated in patients with CRI including 1 patient receiving dialysis, with AEs similar to those in patients without CRI. Eculizumab was associated with a reduction in median LDH from 1783 to 331 U/L (P
- Published
- 2007
- Full Text
- View/download PDF
38. Sustained Improvements in Transfusion Requirements, Fatigue and Thrombosis with Eculizumab Treatment in Paroxysmal Nocturnal Hemoglobinuria
- Author
-
Gérard Socié, Jeff Szer, Russell P. Rother, Jörg Schubert, Peter Hillmen, Robert A. Brodsky, Petra Muus, Ulrich Dührsen, and Antonio M. Risitano
- Subjects
Pediatrics ,medicine.medical_specialty ,Anemia ,business.industry ,Immunology ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Thrombosis ,Treatment period ,Blockade ,Sepsis ,Anesthesia ,medicine ,Paroxysmal nocturnal hemoglobinuria ,business ,medicine.drug - Abstract
The long-term safety and efficacy of eculizumab (Soliris™) were examined in 187 patients with PNH initially enrolled in one of 3 parent trials (N=195) who continued to receive eculizumab in an extension trial for a median of 22 mos. All but 2 patients (99%) who enrolled in the extension trial (Phase 2 Pilot, Phase 3 TRIUMPH and SHEPHERD studies; N=187) were fully blocked at the prescribed dose (900 mg every 14±2 days); adjustment to 1200 mg every 14 days maintained complete complement blockade in the other 2 patients. Clinical benefits of eculizumab were sustained throughout the treatment period. Hemolysis (assessed by LDH) was reduced from a median of 2165 U/L at baseline to 274 U/L at 18 mos (p
- Published
- 2007
- Full Text
- View/download PDF
39. Prevention of Graft-Versus-Host Disease in Mouse Model Using Anti-Mouse C5 Antibody
- Author
-
Nelson J. Chao, Benny J. Chen, Jun-ichi Nishimura, Divino Deoliveira, Yuzuru Kanakura, and Russell P. Rother
- Subjects
biology ,business.industry ,Immunology ,Inflammation ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Isotype ,Complement system ,Complement inhibitor ,medicine.anatomical_structure ,Graft-versus-host disease ,Antigen ,biology.protein ,medicine ,Bone marrow ,Antibody ,medicine.symptom ,business - Abstract
Graft versus-host disease (GVHD) is a major cause of morbidity and mortality after bone marrow transplantation (BMT). An allogeneic GVH reaction is a response of donor lymphoid cells to host minor or major histocompatibility antigens. Donor T cells can be activated through the innate and the adaptive immune mechanisms. Donor B cells produce antibodies directed to host cells. These mechanisms may activate complement pathways. Thus, complement may have a crucial role in inflammation during a GVH reaction, but direct evidence for this has not been shown. In this study, we investigated the possibility of complement inhibitor, anti-mouse C5 antibody (BB5.1), to ameliorate the symptoms of GVHD using an acute GVHD mouse model: C57BL/6 (H2b) →BALB/c (H2d). One million T cells were injected together with 1 x 107 T-cell-depleted bone marrow (TCD BM) cells via tail vein into lethally irradiated BALB/c (8.5 Gy) recipients. Anti-mouse C5 antibody or its isotype matched control was administered intraperitoneally at a dose of 1 mg/mouse, 3 doses/week, for 4 weeks. Recipients were weighed weekly, and their survival was monitored daily. Average body weight of C5 antibody treated mice was 15.8 g at day 84 (19.2 g at day 0, N=12), whereas average weight of control mice was 13.3 g (19.2 g at day 0, N=12) (P=0.05, Student’s t-test). Kaplan-Meier survival curves were also compared as shown in the Figure. Eight of 12 mice were alive at day 84 in the treated group, as compared to only 2 of 12 in the control group (P=0.03, Logrank test). A second experiment showed similar data. We, thus, observed the effect of anti-mouse C5 antibody to reduce the symptoms of GVHD using an acute GVHD mouse model. These results might open a new window for the prevention of acute GVHD. Further experiments are currently ongoing to clarify the exact mechanism between complement and GVHD. Figure Figure
- Published
- 2007
- Full Text
- View/download PDF
40. Human Atheromatous Plaques Stimulate Thrombus Formation by Activating Platelet Glycoprotein VI.
- Author
-
Reininger, Armin J., primary, Brandl, Richard, additional, Penz, Sandra, additional, Goyal, Pankaj, additional, Rabie, Tamer, additional, Rother, Enno, additional, Goetz, Christine, additional, Engelmann, Bernd, additional, Farndale, Richard, additional, Nieswandt, Bernhard, additional, and Siess, Wolfgang, additional
- Published
- 2004
- Full Text
- View/download PDF
41. Sustained Control of Hemolysis and Symptoms and Reduced Transfusion Requirements over a Period of 2 Years in Paroxysmal Nocturnal Hemoglobinuria (PNH) with Eculizumab Therapy.
- Author
-
Hill, Anita, primary, Elebute, Dupe, primary, Marsh, Judith C., primary, Richards, Stephen J., primary, McNutt, Bruce, primary, Petro, Beth E., primary, Rother, Russell P., primary, and Hillmen, Peter, primary
- Published
- 2004
- Full Text
- View/download PDF
42. Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Interim Shepherd Phase III Clinical Study
- Author
-
Neal S. Young, Alvaro Urbano-Ispizua, Hubert Schrezenmeier, Elisabetta Antonioli, Bruno Rotoli, Chieh-Lin Fu, Jaroslaw P. Maciejewski, Luke Coyle, Christopher F. Mojcik, Peter Hillmen, Carlos M. de Castro, Russell P. Rother, and Jörg Schubert
- Subjects
medicine.medical_specialty ,education.field_of_study ,business.industry ,Anemia ,Immunology ,Population ,Area under the curve ,Cell Biology ,Hematology ,Eculizumab ,Interim analysis ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Complement inhibitor ,Internal medicine ,Paroxysmal nocturnal hemoglobinuria ,Medicine ,business ,education ,Adverse effect ,medicine.drug - Abstract
In paroxysmal nocturnal hemoglobinuria (PNH), lack of the GPI-anchored terminal complement inhibitor CD59 from blood cells renders erythrocytes susceptible to chronic hemolysis resulting in anemia, fatigue, thrombosis, poor quality of life (QoL), and a dependency on transfusions. Eculizumab, a terminal complement inhibitor, reduced intravascular hemolysis and transfusion requirements in transfusion dependent patients with normal or near-normal platelet counts in a randomized placebo-controlled trial (TRIUMPH). SHEPHERD, an open-label, non-placebo controlled 52-week phase III clinical study, is underway to evaluate the safety and efficacy of eculizumab in a broader PNH population including patients with significant thrombocytopenia and/or lower transfusion requirements. Eculizumab was dosed as follows: 600 mg IV every 7 days x 4; 900 mg 7 days later; and then 900 mg every 14±2 days. Eculizumab was administered to 97 patients at 33 international sites. In a pre-specified 6-month interim analysis, the most frequent adverse events were headache (50%), nasopharyngitis (23%), and nausea (16%); most were mild to moderate in severity. No infections or serious adverse events were reported as “probably” or “definitely” related to drug. Intravascular hemolysis, the central clinical manifestation in PNH and the primary surrogate efficacy endpoint of the trial, was significantly reduced in eculizumab patients as assessed by change in lactate dehydrogenase (LDH) area under the curve (p
- Published
- 2006
- Full Text
- View/download PDF
43. Treatment with the Terminal Complement Inhibitor Eculizumab Improves Anemia in Patients with Paroxysmal Nocturnal Hemoglobinuria: Phase III Triumph Study Results
- Author
-
Christopher F. Mojcik, Neal S. Young, Jeff Szer, Modupe O. Elebute, Jörg Schubert, Giacomo Gianfaldoni, Russell P. Rother, Petra Muus, Paul Browne, Peter Hillmen, Gérard Socié, and Ulrich Dührsen
- Subjects
medicine.medical_specialty ,Acquired hemolytic anemia ,Anemia ,business.industry ,Immunology ,Area under the curve ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Gastroenterology ,Hemolysis ,Complement inhibitor ,Internal medicine ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Packed red blood cells ,business ,medicine.drug - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a potentially life-threatening acquired hemolytic anemia in which red blood cells (RBCs) lacking complement inhibitory proteins are sensitive to complement-mediated destruction or hemolysis. Intravascular hemolysis in these patients often results in the need for clinical support with packed RBCs (PRBCs) in order to maintain tolerable hemoglobin levels. Eculizumab, a terminal complement inhibitor, has recently been shown in a placebo-controlled randomized phase III clinical trial (TRIUMPH) to reduce intravascular hemolysis and transfusion requirements in patients with PNH. Reported here is a detailed analysis of the effect of eculizumab on various parameters of anemia in these study patients. Eculizumab-treated patients, as compared to placebo, showed an 85.8% decrease in intravascular hemolysis (as measured by LDH area under the curve, p25 units/year, p
- Published
- 2006
- Full Text
- View/download PDF
44. The Terminal Complement Inhibitor Eculizumab Reduces Thrombosis in Patients with Paroxysmal Nocturnal Hemoglobinuria
- Author
-
Robert A. Brodsky, Jeff Szer, Antonio M. Risitano, Hubert Schrezenmeier, Ulrich Dührsen, Scott A. Rollins, Russell P. Rother, Jörg Schubert, Anita Hill, Petra Muus, Leonard Bell, Peter Hillmen, Lucio Luzzatto, Neal S. Young, and Gérard Socié
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Thrombophilia ,Biochemistry ,Gastroenterology ,Thrombosis ,Complement inhibitor ,Internal medicine ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Platelet activation ,Thrombus ,business ,Complication ,medicine.drug - Abstract
Life-threatening thromboembolism (TE) is the most feared complication in patients with paroxysmal nocturnal hemoglobinuria (PNH). Thrombophilia in PNH likely involves a hypercoagulable state, possibly due to intravascular hemolysis with scavenging of the coagulation regulator nitric oxide, and platelet activation. Approximately 45% of PNH deaths result from TE. Thrombosis is more frequent in patients with larger PNH clones, but can occur in patients with smaller clones. Primary prophylactic anti-coagulation may reduce the thrombotic risk in PNH patients, although controlled studies have not been performed and there is a known serious hemorrhage risk. A randomized, placebo-controlled, 26-week phase 3 study of the terminal complement inhibitor eculizumab in 87 PNH patients (TRIUMPH) recently demonstrated dramatic reductions in intravascular hemolysis and RBC transfusions; 1 TE was reported with placebo and 0 with eculizumab. This single study was not powered to examine the effect of eculizumab on TE, and we prospectively examined the aggregate TE event rate in eculizumab-treated patients from TRIUMPH, the two other PNH trials, and the subsequent phase 3 extension study as compared to each patient’s pre-treatment event rate. Before receiving eculizumab, examination of patient records identified 126 TE events in 195 patients, and 103 were on anticoagulants. While pre-treatment TE event rates were variable in the 3 individual PNH studies, eculizumab reduced TE in each study. The TE event rate with eculizumab treatment was 1.22 per 100 patient years, compared to 7.49 (p
- Published
- 2006
- Full Text
- View/download PDF
45. High Definition Contrast-Enhanced MR Imaging in Paroxysmal Nocturnal Hemoglobinuria (PNH) Suggests a High Frequency of Subclinical Thrombosis
- Author
-
Mark T. Gladwin, Scott Reid, Paul O. Collinson, Angela Lowe, Mohan U. Sivananthan, Ashley Guthrie, Russell P. Rother, David Gaze, Peter Hillmen, and Anita Hill
- Subjects
medicine.medical_specialty ,Pathology ,medicine.diagnostic_test ,business.industry ,Immunology ,Warfarin ,Cell Biology ,Hematology ,Hemosiderosis ,medicine.disease ,Biochemistry ,Thrombosis ,Magnetic resonance angiography ,Pulmonary embolism ,Venous thrombosis ,Internal medicine ,medicine ,Cardiology ,Paroxysmal nocturnal hemoglobinuria ,business ,Subclinical infection ,medicine.drug - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by intravascular hemolysis and venous thrombosis. Thrombosis is the most feared complication in PNH and is reported to occur in >40% of patients. Proposed mechanisms of thrombosis include depletion of the coagulation regulator nitric oxide (NO) by intravascular hemolysis and increased sensitivity of PNH platelets to activation. The occurrence of subclinical thrombosis in PNH patients has not been previously studied using modern imaging techniques. In order to evaluate for subclincal thrombosis we evaluated PNH patients with a comprehensive state-of-the-art MRI protocol (which included the use of both blood pool and conventional Gadolinium based contrast agents) for the detection of subclinical thromboses and its sequelae. The detailed protocol consisted of: lung perfusion and pulmonary MRA, cardiac MR - including quantitative studies of both ventricles, right heart flow dynamics and delayed enhancement for the detection of left ventricular damage, and abdominal MR for the assessment of hepatic and portal venous systems and kidneys. 10 PNH patients (median age 31.5 yrs) with large PNH clones but without previous clinical evidence of venous or arterial thrombosis underwent imaging. Five (50%) of the patients were on primary anticoagulant prophylaxis with warfarin. There was evidence of significant renal hemosiderosis, which was distributed throughout the cortices, in 8/10 patients. Two patients had small myocardial scars suggestive of previous unsuspected ischemic damage. Six patients had sub-segmental perfusion defects mainly distributed in the peripheries of the lung fields indicative of previous small pulmonary emboli. No such subclinical thromboses would be anticipated in an age-matched control population. 8 patients had mildly reduced right ventricular ejection fractions (mean 42.2±1.8%; normal range 48–63%). The plasma B-type natriuretic peptide (BNP) level was high in all 10 patients (median 29.4pmol/l; range 18.7–373.90; normal subjects 4.89±1.00pmol/l). BNP has been shown to increase in proportion to right ventricular dysfunction in pulmonary hypertenstion. No intraabdominal defects were identified with the current protocol. In summary, we identified abnormalities suggestive of previous subclinical thromboses in 6 of 10 hemolytic PNH patients by high-resolution MR imaging, including in patients on primary prophylaxis with warfarin. Effective prevention of thrombosis is an important aspect of the therapy in PNH.
- Published
- 2006
- Full Text
- View/download PDF
46. The Effect of Eculizumab Therapy on Red Cell Response Kinetics in Patients with Paroxysmal Nocturnal Hemoglobinuria
- Author
-
Anita J. Dickinson, Russell P. Rother, Matthew J. Cullen, Modupe O. Elebute, Louise Arnold, Peter Hillmen, Anita J. Hill, David Buchanon, and Stephen J. Richards
- Subjects
medicine.medical_specialty ,Red Cell ,business.industry ,Immunology ,Bone marrow failure ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Gastroenterology ,Hemolysis ,Complement inhibitor ,hemic and lymphatic diseases ,Internal medicine ,Paroxysmal nocturnal hemoglobinuria ,medicine ,Erythropoiesis ,Aplastic anemia ,business ,medicine.drug - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by clonal expansion of PNH red cells that are highly sensitive to lysis by terminal complement. The primary lesion in PNH is bone marrow failure in the form of immune-mediated aplastic anemia and peripheral blood cytopenias of varying severity. We have previously reported the successful control of hemolysis and transfusion in 11 patients with the terminal complement inhibitor eculizumab. Ten of these 11 patients remain on eculizumab therapy after approximately 3 years with maintained reductions in intravascular hemolysis and transfusion. The effectiveness of eculizumab therapy in these patients is through the protection of the PNH red cell from complement-mediated lysis and the expansion of this cell population. Flow cytometry studies have shown that the percentage of PNH red cells increased significantly from a mean of 36.7% before treatment to 58.4% at week 64 of therapy. Importantly, granulocyte, monocyte and platelet PNH clone sizes were >90% before treatment and remained stable for all patients throughout the trial suggesting that the majority of hematopoiesis is derived from PNH stem cells. We hypothesize that the PNH red cell clone should approach the clone size of other myeloid hematopoietic cells in a given patient when hemolysis is prevented by eculizumab therapy as this more accurately depicts PNH stem cell activity. Furthermore, the magnitude and rapidity of response in terms of absolute red cell counts is unknown and could potentially provide important insights into the pathophysiology of PNH. In all patients hemolysis was substantially reduced by 21 days. In 9/11 patients, there was a rapid rise in PNH red cell count with the mean absolute number of PNH red cells increasing from 1.37 x 1012/L before treatment to 1.50 x 1012/L at 2 weeks (P=0.21), 1.74 x 1012/L at 4 weeks (P=0.002), and 2.11 x 1012/L at 12 weeks (P=0.001) of eculizumab treatment. The maximum theoretical red cell response was achieved in a mean of 178 days (range 49 – 419 days). The mean absolute number of PNH red cells increased to 2.37 x 1012/L at maximum response (P=0.001), an increase of 73% (range 36% – 207%). All patients achieved a maximum response prior to 18 months of treatment and clone size was subsequently stable. In 2 patients, despite the effectiveness of eculizumab in resolving hemolysis, there was no change in absolute numbers of PNH red cells pre and post-treatment. This is likely due to a combination of a lower degree of hemolysis and more profound bone marrow insufficiency in these patients. The determination of absolute PNH red cell counts during the first 12 months of eculizumab therapy may identify which patients will become transfusion independent and which patients may benefit from additional growth factor support to boost erythropoiesis. Furthermore, long-term eculizumab therapy appeared to be associated with a stable PNH red cell clone size in this initial clinical study.
- Published
- 2005
- Full Text
- View/download PDF
47. Nitric Oxide Consumption and Pulmonary Hypertension in Patients with Paroxysmal Nocturnal Hemoglobinuria
- Author
-
Sara Rollinson, Xunde Wang, Louise Arnold, Peter Hillmen, Alison L. Farrell, Rother P. Russell, Gina M. McGawley, David M. Buchanan, Hilary A. Jessop, Mark T. Gladwin, Anita Hill, David Oxborough, Stephen J. Richards, Robert J. Sapsford, and Paul Pleasants
- Subjects
Hemolytic anemia ,medicine.medical_specialty ,Lung ,medicine.diagnostic_test ,business.industry ,Immunology ,Cell Biology ,Hematology ,Doppler echocardiography ,medicine.disease ,Biochemistry ,Pulmonary hypertension ,Thrombosis ,Surgery ,medicine.anatomical_structure ,medicine.artery ,Internal medicine ,Pulmonary artery ,medicine ,Cardiology ,Paroxysmal nocturnal hemoglobinuria ,business ,Complication - Abstract
Pulmonary hypertension (PHT) is an emerging common complication of hereditary hemolytic anemias. It has been mechanistically and epidemiologically linked to intravascular hemolysis and decreased nitric oxide (NO) bioavailability. While this complication has been described in approximately 30% of adult patients with sickle cell disease and thalassemia, the prevalence of PHT in patients with paroxysmal nocturnal hemoglobinuria (PNH), an acquired disease with the highest levels of intravascular hemolysis observed, has never been determined. PNH patients frequently have symptoms consistent with both hemolysis and PHT including severe fatigue and dyspnea on exertion. Therefore, we examined for the presence of PHT in PNH and explored potential mechanisms associated with its development by measuring the ability of plasma to instantaneously consume NO using ozone-based chemiluminescence. Doppler echocardiography was performed in 24 hemolytic PNH patients to estimate pulmonary artery systolic pressures. Systolic PHT was defined by a tricuspid regurgitant jet velocity (TRV) ≥ 2.5m/s at rest. Eleven (46%) patients had elevated pulmonary artery systolic pressures (mean TRV 2.7m/s ± 0.08) and one (4%) had severely elevated pressures (TRV 3.5m/s). Plasma from PNH patients (n=28) consumed 32.26 ± 8.74μM NO while normal subjects (n=9) consumed 2.42 ± 0.77μM NO (p=0.03). LDH levels correlated with NO consumption (p
- Published
- 2005
- Full Text
- View/download PDF
48. Human Atheromatous Plaques Stimulate Thrombus Formation by Activating Platelet Glycoprotein VI
- Author
-
Richard Brandl, Christine A. Goetz, Tamer Rabie, Richard W. Farndale, Wolfgang Siess, Bernd Engelmann, Enno Rother, Bernhard Nieswandt, Pankaj Goyal, Sandra M Penz, and Armin J. Reininger
- Subjects
chemistry.chemical_classification ,Pathology ,medicine.medical_specialty ,biology ,Immunology ,Hirudin ,Cell Biology ,Hematology ,Heparin ,medicine.disease ,Biochemistry ,Fibrin ,Tissue factor ,chemistry ,medicine ,biology.protein ,Platelet ,Thrombus ,Dense granule ,Glycoprotein ,medicine.drug - Abstract
Lipid-rich atherosclerotic plaques are vulnerable, and upon disruption trigger intraarterial thrombus formation. Tissue factor activating blood coagulation is viewed as the major prothrombotic stimulus within the plaque. We isolated lipid-rich atheromatous plaques from 50 patients with carotid artery stenosis and identified morphologically diverse collagenous structures within in the plaques. They stimulated platelet adhesion, dense granule secretion and aggregation, and triggered thrombus formation in hirudin-anticoagulated blood under arterial flow conditions. Even in fully anticoagulated flowing blood, i.e. in the absence of tissue factor-mediated coagulation, plaques were able to activate platelets. Thrombus formation was more rapid and stable when blood was anticoagulated with a low concentration of heparin, but, although fibrin was detectable within the thrombus, the initial step was always single platelet adhesion and not fibrin formation. In contrast, absence or inhibition of the platelet collagen receptor glycoprotein VI prevented platelet adhesion to atheromatous plaques and thrombus formation. We thus identified platelet glycoprotein VI as being essential and sufficient to mediate plaque-induced thrombus formation. Our study suggests a novel anti-thrombotic strategy to prevent and treat atherothrombosis in patients with vulnerable atherosclerotic plaques. Figure Figure
- Published
- 2004
- Full Text
- View/download PDF
49. Sustained Control of Hemolysis and Symptoms and Reduced Transfusion Requirements over a Period of 2 Years in Paroxysmal Nocturnal Hemoglobinuria (PNH) with Eculizumab Therapy
- Author
-
Bruce McNutt, Judith C. W. Marsh, Beth E. Petro, Dupe Elebute, Stephen J. Richards, Anita Hill, Peter Hillmen, and Russell P. Rother
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Bone marrow failure ,Cell Biology ,Hematology ,CD59 ,Eculizumab ,medicine.disease ,Biochemistry ,Gastroenterology ,Hemolysis ,Surgery ,Venous thrombosis ,Complement inhibitor ,Internal medicine ,Paroxysmal nocturnal hemoglobinuria ,medicine ,Platelet ,business ,medicine.drug - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis and venous thrombosis. Deficiency of the terminal complement inhibitor CD59 from PNH red cells results in complement-mediated hemolysis. Eculizumab, a humanized monoclonal antibody that inhibits terminal complement by binding to C5, is effective at controlling intravascular hemolysis in PNH. We now report that 10 of the 11 patients from an initial 3 month study have continued to receive 900mg eculizumab every other week for 2 years. The remaining patient stopped eculizumab after 23 months despite effective control of intravascular hemolysis, as the patient continued to be transfused even after erythropoietin therapy. This patient had the most severe hypoplasia at the start of eculizumab therapy with a platelet count below 30x109/l, suggesting that the ongoing transfusions were due to the bone marrow failure and not continuing hemolysis. Eculizumab was safe and well tolerated with two reported SAEs in the last year, neither of which were attributed to the drug. The dramatic improvement in various parameters of hemolysis persisted during the 2 year treatment period for all patients. Mean LDH levels decreased from 3111 +/− 598 U/L over the 12 months prior to treatment to 634 +/− 34 U/L up to 24 months following treatment (p=0.002). PNH red cells with a complete deficiency of GPI-linked proteins (Type III red cells) progressively increased during the treatment period from a mean of 36.7% to 58.9% (p=0.001) while partially deficient PNH red cells (Type II) increased from 5.3% to 8.7% (p=0.01). There has been no change in the proportion of PNH neutrophils in any of the patients during eculizumab therapy indicating that the increase in the proportion of PNH red cells is due to a reduction in hemolysis and transfusions rather than a change in the PNH clone(s) itself. The mean and median transfusion rates decreased from 2.1 and 1.8 units/patient/month to 0.4 and 0.3 units/patient/month respectively (p
- Published
- 2004
- Full Text
- View/download PDF
50. Expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B cells confers resistance to human complement
- Author
-
Rother, RP, primary, Rollins, SA, additional, Mennone, J, additional, Chodera, A, additional, Fidel, SA, additional, Bessler, M, additional, Hillmen, P, additional, and Squinto, SP, additional
- Published
- 1994
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.