Clinical Trials

Date: 2015-11-07

Type of information: Presentation of results at a congress

phase:

Announcement: presentation of results at the 2015 American Society of Nephrology (ASN) Annual Meeting in San Diego

Company: Alexion Pharmaceuticals (USA - CT)

Product: Soliris® (eculizumab)

Action mechanism:

• monoclonal antibody. Eculizumab is a recombinant humanized monoclonal IgG2/4 antibody that specifically binds to the complement protein C5, inhibiting its cleavage by the C5 convertase which prevents the generation of the terminal complement complex C5b-9.

Disease: atypical hemolytic uremic syndrome (aHUS)

Therapeutic area: Rare diseases - Kidney diseases

Country:

Trial details:

Latest news:

• • On November 7, 2015, Alexion Pharmaceuticals announced that researchers presented new data from a long-term follow-up study evaluating the effectiveness and safety of Soliris® (eculizumab) in preventing thrombotic microangiopathy (TMA) in patients with atypical hemolytic uremic syndrome (aHUS). In this observational study, researchers reported a 74 percent lower TMA event rate with ongoing Soliris®treatment with labeled dosing compared with discontinuation of Soliris therapy. These data were presented at the 2015 American Society of Nephrology (ASN) Annual Meeting in San Diego . Jan Menne , M.D., of Hannover Medical School , Hannover, Germany , presented results from an ongoing, long-term follow-up study evaluating the rate and severity of TMA events during treatment with Soliris and following discontinuation of Soliris treatment in patients with aHUS. The study included 87 patients who had been treated with Soliris in any of five previous clinical studies. Seventy-six patients had on-treatment periods (median 45.9 months) and 39 patients had off-treatment periods (median 20.1 months) during this observational trial. For the primary endpoint, researchers reported that the TMA event rate was 63 percent lower during periods of Soliris treatment compared to periods of treatment discontinuation. Additionally, the rate of TMA events during periods of on-label dosing of Soliris was 74 percent lower than during periods of treatment discontinuation, and was also 57 percent lower compared with periods when patients were on treatment but receiving non-labeled dosing. Moreover, off-treatment periods were more frequently associated with serious adverse events and hospitalizations related to TMA events compared with on-treatment periods. There were no unexpected safety signals reported during the observational study period, and treatment-emergent adverse event rates were similar between the two groups. One adult patient from parent study C10-004 died during the observational study due to intensive care complications and multi-organ failure determined to be caused by coexisting disease and unrelated to Soliris. Two patients from parent study C09-001 reported meningococcal infections during the observational study; both were determined to be probably related to Soliris. Both patients recovered and no changes to Soliris dosing were made. Additional studies presented at ASN included a post-hoc analysis evaluating the safety of Soliris in pediatric and adolescent patients with aHUS and an update from the Global aHUS Registry. Gema Ariceta, M.D., Ph.D., of the Hospital Universitario Materno-Infantil Vall d' Hebron , Barcelona , presented a post-hoc analysis of safety data from three prospective clinical trials in 28 pediatric ( < 12 years of age) and adolescent (12-17 years of age) patients with aHUS treated with Soliris. Most treatment-emergent adverse events (TEAEs) reported in the analysis were mild to moderate in severity. Of the patients experiencing TEAEs, half (n=13) had events determined to be at least possibly related to Soliris (TRAEs). The most common TRAEs reported by 1 year of Soliris treatment were skin/subcutaneous tissue disorders including alopecia, dermatitis, eczema, erythema and rash, and infections/infestations including ear infection, fungal infection, nasopharyngitis, and oral fungal infection. Four patients reported serious TRAEs by 1 year of treatment, including infections and agitation. By end of study (mean 67 weeks), 6 infection-related serious TRAEs occurred in 4 patients, including viral upper respiratory tract infection (n=2), influenza peritonitis, respiratory syncytial virus infection, and pyelonephritis (n=1 each). No unexpected TRAEs were noted and no deaths or meningococcal infections were reported. Although infections were the most commonly observed TRAEs, most were mild to moderate in severity and expected in a pediatric population, none led to treatment discontinuation, and all patients recovered. Researchers concluded that treatment with Soliris is well tolerated in pediatric patients with aHUS, with a safety profile consistent with the broader patient population of the clinical trial program.
• • On November 16, 2014, Alexion Pharmaceuticals announced that researchers presented data from clinical trials of Soliris® (eculizumab) in patients with atypical hemolytic uremic syndrome (aHUS), as well as an update from the Global aHUS Registry, at Kidney Week 2014, the annual meeting of the American Society of Nephrology, in Philadelphia. These data, from a total of seven presentations, continue to enhance the understanding of aHUS and underscore the effectiveness of sustained Soliris treatment in children and adults with aHUS. The following posters were presented  at Kidney Week 2014:
• Eculizumab Inhibits Thrombotic Microangiopathy and Improves Renal Function in Adult Atypical Hemolytic Uremic Syndrome Patients: 1-Year Update (Poster SA-PO508) Fadi Fakhouri M.D., Ph.D., of Centre Hospitalier Universitaire de Nantes in Nantes, France, presented outcomes from a 1-year update of the largest prospective study (Study C10-004) of Soliris in adult patients with aHUS (N=41). In this open-label, single-arm trial, the primary endpoint of complete TMA response—defined as platelet count normalization, LDH normalization and preservation of renal function—was achieved by 30 patients receiving Soliris (73%) at 26 weeks and by 33 patients (80%) at 1 year. Patients also had continued improvement in renal function with sustained Soliris treatment, with 22 patients (54%) achieving an improvement in estimated glomerular filtration rate (eGFR) from baseline of ?15 mL/min/1.73 m2 at 26 weeks and25 patients (61%) achieving this endpoint at 1 year.
• There were no unexpected safety signals in the one-year study period. The most common drug-related adverse events (AEs) at 1 year were alopecia (7%), asthenia (5%), arthralgia (5%) and pain in extremity (5%). Two patients in the C10-004 study had meningococcal infections, both during the 26-week study period. One patient discontinued from the study and later recovered; the other continued treatment with no interruption and recovered without sequelae. No additional meningococcal infections were reported between 26 weeks and 1 year.
• Time to End-Stage Renal Disease in Patients with Atypical Hemolytic Uremic Syndrome Receiving Supportive Care and Eculizumab (Poster SA-PO509): Researchers also presented an analysis that retrospectively evaluated the decline in renal function and progression to ESRD in patients in the pretreatment period of two clinical trials and compared this to the time to progression to ESRD in the same patients after beginning treatment with Soliris. Patients in the pretreatment period received supportive care, defined as plasma exchange/plasma infusion (PE/PI), dialysis and/or kidney transplant. In the analysis, patients receiving Soliris (N=33) had a 97% reduction in the risk of progression to ESRD over 3 years compared with the risk of progression to ESRD in patients receiving supportive care only (N=32). Additionally, over 3 years, no patient who initiated Soliris in chronic kidney disease (CKD) stage 2 or 3 progressed to ESRD, and the risk of progression for patients who initiated Soliris treatment in CKD stage 4 was reduced by 92% compared to the risk of progression in patients receiving supportive care only . These results are consistent with outcomes reported in prior clinical trials, in which patients with aHUS had improvements in renal outcomes and elimination of dialysis during ongoing treatment with Soliris.
• Safety and Efficacy of Eculizumab in Pediatric Patients With aHUS, With or Without Baseline Dialysis (Poster SA-PO546)
• Johan Vande Walle, M.D., Ph.D., of the University of Ghent, Belgium, presented results from a post-hoc sub-analysis of an open-label single-arm trial (C10-003), evaluating the safety and efficacy of Soliris in pediatric patients with aHUS with and without a history of dialysis at baseline (N=22). In this study, complete TMA response (defined as platelet count normalization, LDH normalization and improvement of renal function) was achieved in 55% (6/11) of patients with baseline dialysis and 73% (8/11) of patients with no baseline dialysis. Dr. Vande Walle also reported mean eGFR improvement from baseline of +57.7 mL/min/1.73 m2 for patients with baseline dialysis and +70.3 mL/min/1.73 m2 for patients with no baseline dialysis. Researchers concluded that Soliris treatment was efficacious in patients with aHUS regardless of dialysis history.3
• There were no unexpected safety signals reported during the analysis period, and no meningococcal infections were reported in the C10-003 study. The most common AEs reported by subgroup were: for patients with baseline dialysis, pyrexia (54.5%), respiratory tract infection (36.4%), and cough (36.4%); for patients without baseline dialysis, pyrexia (45.5%), abdominal pain (36.4%), cough (36.4%), diarrhea (36.4%), and nasopharyngitis (36.4%).
• Safety and Efficacy of Eculizumab in Adult Patients With aHUS, With or Without Baseline Dialysis (Poster SA-PO507): Dr. Fakhouri presented results from a post-hoc sub-analysis from the C10-004 study that evaluated the safety and efficacy of Soliris in adult patients with aHUS with and without a history of dialysis at baseline (N=41). In this study, complete TMA response was achieved in 71% (17/24) of patients with baseline dialysis and 77% (13/17) of patients with no baseline dialysis. He also reported mean eGFR improvement from baseline of +35.0 mL/min/1.73 m2 for patients with baseline dialysis and +20.0 mL/min/1.73 m2 for patients with no baseline dialysis. Researchers concluded that Soliris treatment was efficacious in patients with aHUS regardless of dialysis history. There were no unexpected safety signals reported during the analysis period. As previously described, two patients in the C10-004 study had meningococcal infections (one patient discontinued from the study and later recovered; the other continued treatment with no interruption and recovered without sequelae). The most common AEs reported by subgroup were: for patients with baseline dialysis, headache (33.3%), diarrhea (29.2%), and hypotension (20.8%); for patients without baseline dialysis, headache (41.2%), diarrhea (35.3%), and asthenia (29.4%).
• Safety and Efficacy of Eculizumab in Adult aHUS Patients, With or Without Renal Transplant (Poster SA-PO511): Chantal Loirat, M.D., of the Hôpital Robert Debre, Paris, presented a post-hoc sub-analysis from the C10-004 study that evaluated the safety and efficacy of Soliris in adult patients with aHUS (N=41) with and without a history of renal transplant. In the study, complete TMA response was achieved in 78% (25/32) of non-transplant patients and in 56% (5/9) of transplant patients. In addition, non-transplant patients had a mean eGFR improvement of +31.5 mL/min/1.73 m2 from baseline, while transplant patients had a mean improvement of +19.0 mL/min/1.73 m2. Dr. Loirat concluded that these data provide additional support for the early initiation of Soliris in both transplant and non-transplant patient with aHUS. There were no unexpected safety signals reported during the analysis period. As previously described, two patients in the C10-004 study developed meningococcal infections (one patient discontinued from the study and later recovered; the other continued treatment with no interruption and recovered without sequelae). The most common AEs reported by sub-group were: for patients with renal transplant, diarrhea (55.6%), anemia (44.4%), urinary tract infection (33.3%), renal impairment (33.3%), and hematoma (33.3%); for patients without renal transplant, headache (40.6%), peripheral edema (28.1%), diarrhea (25.0%), and cough (25.0%).
• Characteristics of 521 Adult and Pediatric Patients in the Global aHUS Registry (Poster SA-PO510): Christoph Licht, M.D., FASN, of The Hospital for Sick Children, Toronto, presented baseline demographics from patients enrolled in the global aHUS Registry, which is dedicated to increasing the understanding and awareness of aHUS to help optimize care and improve quality of life for patients. As of August 2014, 521 patients had enrolled in the registry.6
• Eculizumab Reduces Markers of Complement Activation, Inflammation, Thrombosis and Endothelial Activation and Damage: Correlation with Improved Renal Function in Patients with Atypical Hemolytic Uremic Syndrome (SA-PO506): Important biomarker data from a prospective, open-label trial of adult patients (N=41) with aHUS treated with Soliris were also reported today. The study authors reported that at baseline, prior to initiation of Soliris, patients with aHUS showed significant elevation in levels of markers of proximal and terminal complement activation, inflammation, coagulation, and endothelial cell activation and damage regardless of CKD stage or dialysis. Sustained Soliris treatment significantly reduced and normalized highly elevated measures of terminal complement activation, and resulted in:
• Significant reduction in markers of inflammation (sTNFR1) by up to 94%; reduction after week 6 was sustained and significant across all later time points (P<0.0001) Significant reduction in markers of coagulation (D-dimer) by up to 99%; reduction was sustained (PSignificant reduction in markers of endothelial damage (thrombomodulin) (P<0.0001) to near normal levels; reduction was significant across all later time points (P<0.0001) after week 17 Markers of proximal complement (Ba) upstream of C5, and markers of endothelial activation (sVCAM-1) were also reduced but remained above those of healthy volunteers, reflecting ongoing dysregulation of complement in aHUS and the need for sustained terminal complement blockade.

Is general: Yes