Alexion Pharmaceuticals to Present Data on Soliris(R) (Eculizumab) and PNH at the 2007 American Society of Hematology (ASH) Annual Meeting
CHESHIRE, Conn., Nov 09, 2007 /PRNewswire-FirstCall via COMTEX News Network/ -- Alexion Pharmaceuticals, Inc. (Nasdaq: ALXN) today announced that data relating to paroxysmal nocturnal hemoglobinuria (PNH), as well as to Soliris(R) (eculizumab) as a treatment for patients with PNH, have been published by the American Society of Hematology (ASH). Abstracts will be presented at the 2007 ASH annual meeting that is being held December 8 to 11, 2007 at the Georgia World Congress Center in Atlanta.
The following abstracts will be presented in a poster session on red cell regulation and disorders of production on Monday, December 10, 2007. The abstracts and presentation information can be accessed at the links provided below.
-- "High Incidence of Progression to Chronic Renal Insufficiency in
Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)" Dr. Peter
Hillmen et al.
abstracts2view.com
-- "Sustained Improvements in Transfusion Requirements, Fatigue and
Thrombosis with Eculizumab Treatment in Paroxysmal Nocturnal
Hemoglobinuria" Dr. Gerard Socie et al.
abstracts2view.com
-- "Disease.Related Symptoms Reported across a Broad Population of
Patients with Paroxysmal Nocturnal Hemoglobinuria" Dr. Gabrielle
Meyers et al.
abstracts2view.com.
The following abstract will be presented in an oral session on red cell regulation and disorders of production on Tuesday, December 11, 2007. The abstract and presentation information can be accessed at the link provided below.
-- "Significant Disease Burden in Paroxysmal Nocturnal Hemoglobinuria
Patients with Lower Levels of Hemolysis, Mild Anemia and Minimal
Transfusion: Clinical Improvement with Eculizumab Therapy" Dr. Monica
Bessler et al.
abstracts2view.com.
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[3678] High Incidence of Progression to Chronic Renal Insufficiency in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Session Type: Poster Session, Board #897-III
Peter Hillmen, Modupe O. Elebute, Richard Kelly, Alvaro Urbano-Ispizua, Russell P. Rother, Chieh-Lin Fu, Paul Browne General Infirmary, Leeds, United Kingdom; St. George Hosp., London, United Kingdom; Hosp. Clinic i Provincial, Barcelona, Spain; Alexion Pharmaceuticals, Cheshire, CT, USA; Cleveland Clinic, Weston, FL, USA; St James Hosp., Dublin, Ireland
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<.0001) and reduction in thrombosis from 5.34 to 0.00 thrombotic events/100 pt-years (P<.0001) in patients with CRI. For patients with baseline CRI, GFR remained stable (median increase 0.47 ml/min/1.73m2) and 10% of patients were no longer classified as CRI, with eculizumab treatment. For the 14 patients with ARF pre-eculizumab, only one patient was reported with ARF during eculizumab (P<.001). CRI is a common finding in PNH as the observed prevalence in hemolytic PNH patients is increased 5-fold compared to the prevalence in the overall U.S. population [NEJM 2006;354:2473-83]. ARF is a specific risk factor for development of CRI, although it is not a sensitive risk indicator as most patients with CRI did not previously have ARF. These data suggest that all PNH patients should be closely monitored for CRI and that hemolysis and/or microvascular thrombosis are risk factors for CRI. In the current studies of hemolytic PNH patients, CRI was associated with both increased duration of PNH and duration of exposure to thrombotic events. Eculizumab is safe and effectively reduces hemolysis and thrombosis in PNH patients with ARF and CRI. Moreover, as eculizumab controls hemolysis, reduces thrombosis, and reduces re-occurrence of ARF, the long-term impact of eculizumab on the prevention of renal pathology and CRI in patients with PNH will continue to be evaluated.
Abstract #3678 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Paroxysmal Nocturnal Hemoglobinuria (PNH)|Renal Impairment|Hemolysis
Monday, December 10, 2007 5:00 PM
Session Info: Poster Session: Red Cell Regulation and Disorders of Production (5:00 p.m.-7:00 p.m.)
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[3672] Sustained Improvements in Transfusion Requirements, Fatigue and Thrombosis with Eculizumab Treatment in Paroxysmal Nocturnal Hemoglobinuria. Session Type: Poster Session, Board #891-III
Gerard Socié, Peter Hillmen, Petra Muus, Jörg Schubert, Ulrich Dührsen, Antonio M. Risitano, Russell P. Rother, Robert A. Brodsky, Jeffrey Szer Hop. Saint Louis and INSERM, Paris, France; General Infirmary, Leeds, United Kingdom; Radboud Univ., Nijmegen, Netherlands; Saarland Univ., Homburg, Germany; Univ., Essen, Germany; Federico II Univ., Naples, Italy; Alexion Pharm., Cheshire, CT, USA; Johns Hopkins, Baltimore, MD, USA; Royal Melbourne Hospital, Melbourne, Australia
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 142 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<0.001, n=171), and 277 U/L at 54 mos (p=0.002, n=10). Transfusion requirements decreased from a median of 8 units (mean 8.7) during the 6 mos pre-treatment period to 0 units (mean 3.3) during the first and 0 (mean, 2.8) during the most recent 6 mos of eculizumab (p<0.001 for each). FACIT-Fatigue instrument showed a median increase from baseline of 4.7 points in the first 6 mos (n=174) and a further improvement to 7.1 points in the most recent 6 mos (n=166) of treatment (p<0.001 for each); an increase of 3 or more points is considered clinically meaningful. Multivariate analysis indicated that reduction in hemolysis was predictive of improvement in fatigue, independent of improvement in anemia (p=0.028). Improvements in global health, patient functioning, pain and dyspnea continued (p0.011; EORTC QLQ-C30). Reduction of thromboembolism (TE) with eculizumab was maintained. In matched time periods pre and post treatment, the TE event rate was reduced 90% from 12.53 (45 events/359 patient yrs) to 1.31 events/100 patient yrs (5 events/382 patient yrs, p<0.001). The TE event rate was also reduced 91% (10.61 to 0.93 events/100 patient yrs) for patients receiving concomitant antithrombotics (p<0.001, n=103). Eculizumab was well tolerated. Patients who discontinue eculizumab therapy should be monitored for risk of serious hemolysis; 16 patients discontinued treatment and none experienced serious hemolysis (LDH above pretreatment levels with adverse sequelae). Rates of infection-related AEs and serious AEs were similar for the first 6 mos (75.4%, 3.7%, respectively) and most recent 6 mos (64.2%, 5.9%) of treatment and were similar to 6 mos of placebo treatment in the TRIUMPH study (77.3%, 11.4%). Rates of sepsis-related AEs were similar for the first and most recent 6 mos (1.1% for each). All patients were vaccinated against Neisseria meningitidis; during 382 patient yrs of treatment, there were 2 cases of meningococcal septicemia (0.52 per 100 patient yrs) which were promptly treated and recovered without sequelae. The most common AEs were headache (55%), nasopharyngitis (46%), and upper respiratory tract infection (40%). SAEs were reported by 33% of patients; rates were similar during the first and most recent 6 mos of treatment (11% and 12%, respectively) and were less than that during 6 mos of placebo treatment (20%).These findings demonstrate that long-term eculizumab therapy provides sustained clinical benefit to and is well tolerated by patients with PNH.
Abstract #3672 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Paroxysmal Nocturnal Hemoglobinuria (PNH)|Thrombosis|Fatigue
Monday, December 10, 2007 5:00 PM
Session Info: Poster Session: Red Cell Regulation and Disorders of Production (5:00 p.m.-7:00 p.m.)
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[3683] Disease-Related Symptoms Reported across a Broad Population of Patients with Paroxysmal Nocturnal Hemoglobinuria. Session Type: Poster Session, Board #902-III
Gabrielle Meyers, Ilene Weitz, Thierry Lamy, Jean-Yves Cahn, Henk-André Kroon, Beth Severino, Maria Teresa Uranga, Miguel Sanz Alonso, José Antonio García Vela, Anita Hill Oregon Health and Science Univ., Portland, OR, USA; Keck-USC School of Med., Los Angeles, CA, USA; Pontchaillou Hosp., Rennes, France; Hpital Michallon, Grenoble, France; Alexion Pharmaceuticals, Inc., Cheshire, CT, USA; Hosp. Donosita, San Sebastian, Spain; Univ. Hospital La Fe, Valencia, Spain; Univ. Hosp. Getafe, Madrid, Spain; General Infirmary, Leeds, United Kingdom
In paroxysmal nocturnal hemoglobinuria (PNH), lack of the GPI-anchored terminal complement inhibitor CD59 from erythrocytes renders them susceptible to chronic hemolysis, which is central to the signs and symptoms of PNH. Patients are at elevated risk for thrombosis, experience anemia that may require transfusion support, and suffer from fatigue that can be severe. Patients often have a poor quality of life resulting from PNH related symptoms including pain, dyspnea, dysphagia and erectile dysfunction, which negatively impact quality of life. The prevalence and severity of symptoms were explored in the context of a multi-national content validation study, of patients not receiving eculizumab therapy, employing the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) instruments. Symptom questions were asked of 29 PNH patients (19 men, 10 women, mean age 41.213.2 years) from the United Kingdom, United States, France and Spain. More than half (52%) had PNH for over 5 years. Most (76%) reported never having had a blood clot, 31% reported not receiving any medication for their PNH, and 59% reported either that they had never been transfused or had not received transfusion within the last year for PNH. Patients viewed overall quality of life, global health, functioning, fatigue, pain, and shortness of breath as important PNH-related signs/symptoms. Both the FACIT-Fatigue and EORTC instruments were relevant and adequate in assessing the level of fatigue and other quality of life measures in PNH. The burden of disease in this multicultural and diverse cohort of patients was significant: 76% were forced to modify their daily activities to manage their PNH and 17% were unemployed due to PNH. Nearly all (96%) complained of fatigue and more than half reported abdominal pain, headache and shortness of breath (Table). Patients also commonly reported dysphagia (41%) and erectile dysfunction (47% in males). Most patients reported these PNH-related symptoms as moderate to very severe, and a substantial majority reported distress associated with the symptoms. Significant disease burden was identified in a diverse population of PNH patients, most of which had minimal or no transfusion requirements and a low incidence of thrombosis. Therapy that controls hemolysis and thereby improves fatigue, pain, shortness of breath, dysphagia and erectile dysfunction may prove beneficial for PNH patients with these disease characteristics.
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[840] Significant Disease Burden in Paroxysmal Nocturnal Hemoglobinuria Patients with Lower Levels of Hemolysis, Mild Anemia and Minimal Transfusion: Clinical Improvement with Eculizumab Therapy. Session Type: Oral Session
Monica Bessler, Hubert Schrezenmeier, Jaroslaw P. Maciejewski, Anita Hill, Scott A. Rollins, Neal S. Young, Lucio Luzzatto Washington Univ. School of Med., St. Louis, MO, USA; Institute of Clinical Transfusion Medicine and Immunogenetics, Ulm, Germany; Cleveland Clinic, Cleveland, OH, USA; Leeds General Infirmary, Leeds, United Kingdom; Alexion Pharmaceuticals, Cheshire, CT, USA; National Heart, Lung, and Blood Institute, Bethesda, MD, USA; Istituto Toscano Tumori, Florence, Italy
Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening disease. However, disease burden in patients with lower lactate dehydrogenase (LDH), higher hemoglobin and minimal transfusion support has not been determined. The terminal complement inhibitor, eculizumab (Soliris), was shown to significantly reduce hemolysis, improve anemia and fatigue, and reduce thrombosis in a broad PNH population. We examined the long-term efficacy of eculizumab in multiple patient subgroups. Efficacy data included hemolysis (as assessed by LDH), transfusion requirements, fatigue (measured by Functional Assessment of Chronic Illness Therapy-Fatigue instrument, FACIT-Fatigue), and thrombosis. Data were analyzed by lower baseline hemolysis (LDH <1490 U/L, n=46), mild anemia (Hgb 10.5 g/L, n=54), and minimal transfusion (0 or 1 episodes in prior yr, n=21) among 187 PNH patients who had been enrolled in eculizumab trials (Phase 2 Pilot, Phase 3 TRIUMPH and SHEPHERD studies) and who continued to receive eculizumab in a long-term extension trial (median duration, 22 months). Eculizumab provided significant clinical benefit to patients regardless of baseline degree of hemolysis, anemia, or transfusion requirement (Table). Fatigue improved with eculizumab across all baseline LDH quartiles. Of interest, reduced hemolysis with eculizumab improved fatigue even in patients with only mild anemia and little or no transfusion requirement, suggesting that lowering hemolysis improves fatigue, independent of anemia. Fatigue scores increased during the first 6 mos of treatment and continued to improve throughout the last six months of treatment. Transfusion requirements also maintained during long-term treatment; patients requiring >1 transfusion in the year prior received a median of 8.5 units in the 6 months prior to eculizumab, 2.0 units in the first 6 months of treatment, and 0 units in the last 6 months of treatment. In patients with evidence of marrow failure (n=25; platelets <100,000/mm3 and no prior thrombosis) compared with pre-treatment, hemolysis (LDH) was reduced by 1217211 U/L, median units transfused were reduced from 8 (mean 9.21.2) to 0 (4.41.4) and fatigue improved by 8.12.1 points (p0.001 for each) during the last six mos of eculizumab therapy. Thromboembolism (TE) was examined in all eculizumab trial patients (N=195). The TE rate was elevated in the pre-treatment period for patients with lower baseline hemolysis, mild anemia and minimal transfusion; eculizumab reduced TE in these patient subgroups by 58% (p=0.009, n=48), 84% (p<0.001, n=55) and 100% (p=0.063, n=22), respectively. In conclusion, patients who may be expected to have less severe disease suffer from significant disease burden, and long-term treatment with eculizumab provides substantial clinical improvement.
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