Clinical Trials

Date: 2014-09-19

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the 53rd Annual European Society for Paediatric Endocrinology (ESPE) Meeting in Dublin, Ireland

Company: Alexion Pharmaceuticals (USA - CT)

Product: asfotase alfa (alkaline phosphatase)

Action mechanism:

• enzyme replacement therapy. Asfotase alfa is an investigational, highly innovative, first-in-class targeted alkaline phosphatase enzyme replacement therapy. Asfotase alfa is designed to address the underlying cause of HPP by normalizing the genetically defective metabolic process, and preventing or reversing the severe and potentially life-threatening complications of life-long dysregulated mineral metabolism.

Disease: hypophosphatasia

Therapeutic area: Bone diseases - Genetic diseases - Metabolic diseases

Country:

Trial details:

 

Latest news:

• • On September 19, 2014, Alexion Pharmaceuticals announced that researchers presented data from the open-label extension phases of two Phase 2 studies of asfotase alfa in paediatric patients with hypophosphatasia (HPP). Data were presented at the 53rd Annual European Society for Paediatric Endocrinology (ESPE) Meeting in Dublin, Ireland, following a presentation of similar data earlier this month at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting (see below). In the ongoing studies, researchers observed sustained improvements in growth, strength, physical function, and other key measures in paediatric patients with HPP who were treated with asfotase alfa for up to three years. In an oral presentation, researchers reported that severely affected infants and young children with HPP (aged ?3 years at study entry, N=11) treated with asfotase alfa for up to three years experienced sustained improvements in growth and physical function. Findings were from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in severely affected infants with HPP. In the data presented at ESPE, investigators observed that patients treated with asfotase alfa had improvement in weight as measured by Z-score. Median weight Z-score was -3.8 at baseline; over the course of treatment, median change from baseline in Z-score steadily increased from +0.6 at one year to +2.6 at three years. Additionally, as reported at ASBMR, improvement in growth as measured by height/length Z-score was also observed in treated patients. Median height/length Z-score was -3.7 at baseline, indicating marked delay relative to peers; over the course of treatment, median change from baseline in Z-score steadily increased from +1.2 at one year to +2.3 at three years. Patients treated with asfotase alfa also had gains in gross motor function, fine motor function and cognitive function. Asfotase alfa was generally well-tolerated in the extension study. The most common adverse events were pyrexia (7/10), mild or moderate injection-site reactions (6/10) and upper respiratory tract infection (6/10). Three serious AEs were reported as possibly related to treatment: craniosynostosis, conductive deafness and mild chronic hepatitis. Both craniosynostosis and conductive deafness were reported in the same patient, and are findings previously described as associated with HPP. The report of hepatitis was in a patient taking a medication for asthma, which was discontinued; liver function tests were within normal limits at last assessment. Four patients tested positive for neutralizing antibodies, without apparent impact on treatment efficacy or safety. In a separate oral presentation, researchers also reported that children with HPP (aged 5-12 at study entry, N=13) who were treated with asfotase alfa experienced significant gains in height and rapid and sustained improvements in strength, agility, and physical function. The data were from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in HPP patients. In the data presented at ESPE, researchers reported improvements in right hip abductor muscle strength over the course of treatment, from 48% predicted at baseline to 83% predicted at last assessment (p=0.001). Additionally, and as reported at ASBMR, improvement in growth, as measured by height Z-score, was observed in treated patients, from a median of -1.26 at baseline to a median of -0.72 at last assessment (p=0.0027). Improvements in strength and agility were also observed for treated patients as measured by the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2). BOT-2 composite standardized score improved from a median of 28 at baseline to a median of 50 at last assessment (p<0.0008), which is the mean score for normal, healthy peers. Asfotase alfa was generally well-tolerated in the study. The most common AEs were mild or moderate injection site reactions. There were no deaths, serious AEs or withdrawals due to AEs over the three years of treatment in this study. Twelve patients tested positive for anti-asfotase antibodies, two of whom had neutralizing antibodies with no apparent effect on efficacy or safety.
• • On September 14, 2014, Alexion Pharmaceuticals announced that researchers presented new data from an integrated analysis of survival from two open-label, Phase 2 studies of asfotase alfa in pediatric patients (ages ?5 years at enrollment) with hypophosphatasia (HPP) compared with data from a retrospective natural history study of untreated historical control patients matched for age and disease severity. In this analysis, survival in patients with HPP at high risk of death who were treated with asfotase alfa for up to five years was significantly improved (89% vs. 27%, p<0.0001) compared with untreated historical control patients.These late-breaking results were presented  at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting in Houston, where researchers also presented new data from the ongoing open-label extension phases of two Phase 2 clinical studies in which sustained gains in physical function and reductions in disability and pain were observed in pediatric patients receiving asfotase alfa treatment for up to three years.
• Survival Data from Studies of Asfotase Alfa in Severely Affected Pediatric Patients Compared With Historical Controls (Abstract 1097): In an oral session today, researchers reported that treatment with asfotase alfa significantly improved survival in pediatric patients (ages ?5 years at enrollment) with severe HPP.1 Over the five-year analysis period, 89% (33/37) of patients treated with asfotase alfa survived compared with 27% (13/48) of untreated historical control patients. Invasive ventilator-free survival was also significantly improved in treated patients (p<0.0001); 83% (21/25) of treated patients required no invasive ventilation and survived, compared with 25% (12/48) of historical control patients. These results were from an integrated analysis of survival from two multicenter, open-label, ongoing Phase 2 studies of patients with HPP who were treated with asfotase alfa, compared with data from a retrospective natural history study of untreated historical controls, matched for age and disease severity. Findings from the retrospective natural history study were previously reported at the Pediatric Academic Societies (PAS) meeting in May 2014.9 Patients in the asfotase alfa trials were five years of age or younger at enrollment and had been diagnosed with HPP prior to six months of age. Included in the survival analysis were patients who had one or more of the following signs of severe HPP: rachitic chest, history of respiratory distress, or Vitamin B6-responsive seizures. Median duration of treatment was two years, with patients treated for up to five years. Investigators also reported the following results: • Among patients with rachitic chest at baseline, 90% (27/30) of treated patients survived compared with 33% (13/40) of historical controls • Among patients with history of respiratory compromise, 89% (24/27) of treated patients survived compared with 18% (7/40) of historical controls • Among patients who experienced Vitamin B6-responsive seizures, 85% (11/13) of treated patients survived compared with 0% (0/10) survival for historical controls.
• Asfotase Alfa in Infants and Young Children with Life-Threatening HPP: New Extension Study Results (Abstract FR0435): In an oral poster, Dr. Whyte and colleagues reported that severely affected infants and young children with HPP (age ?3 years at study entry, N=11) treated with asfotase alfa for up to three years experienced sustained improvement in growth and physical function.2 Findings were from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in severely affected infants with HPP. Data from this study were previously presented by investigators at the PAS meeting in May 2014. Patients (N=11) had early (3 months, p=0.03) and sustained (3 years, p=0.008) bone healing as measured by the radiographic global impression of change (RGI-C) scale and the rickets severity scale (RSS). While 10 patients required respiratory support at or soon after entry into the study, only one patient continued to require respiratory support (supplemental oxygen) at the last assessment. Researchers reported a three-year survival rate of approximately 90%. New data presented at ASBMR included the following: • For patients treated with asfotase alfa, improvement in growth as measured by height/length Z-score was observed. Median height/length Z-score was -3.7 at baseline, indicating marked delay relative to peers; over the course of treatment, median change from baseline in Z-score steadily increased from -0.3 at three months to +2.3 at three years. • In asfotase alfa treated patients, improvement in functional development was observed as measured by the Bailey’s Scales of Infant and Toddler Development 3rd Edition (BSID-3), with all evaluable patients (N=9) demonstrating increases in age-equivalent scores, indicating acquisition of new gross motor, fine motor and cognitive skills during treatment. Asfotase alfa was well-tolerated in the extension study. The most common adverse events (AEs) were pyrexia (7/10), mild or moderate injection-site reactions (6/10) and upper respiratory tract infection (6/10). Three serious AEs were reported as possibly related to treatment: craniosynostosis, conductive deafness and mild chronic hepatitis. Both craniosynostosis and conductive deafness were reported in the same patient, and are findings previously described as associated with HPP. The report of hepatitis was in a patient taking a medication for asthma, which was discontinued; liver function tests were within normal limits at last assessment. Four patients tested positive for neutralizing antibodies, without apparent impact on treatment efficacy or safety.
• Asfotase Alfa in Juveniles with HPP: New Extension Study Results (Abstract 1081): In an oral plenary session, Katherine L. Madson, M.D., Ph.D., from the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children, St. Louis, reported that children with HPP (N=13) who were treated with asfotase alfa experienced significant growth, rapid improvements in physical function, and decreases in disability and pain that were sustained over a period of three years. The data were from the extension phase of a multinational, open-label Phase 2 study of asfotase alfa treatment in HPP patients aged 5-12 at study entry. Improvements in bone healing as measured by RGI-C and in two measures of physical function—distance walked in six minutes and strength and agility as measured by the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2) composite score—were observed in data presented earlier this year at PAS. New data presented at ASBMR showed the following: • In patients treated with asfotase alfa, a significant and clinically meaningful decrease in disability was observed, as measured by the Child Health Assessment Questionnaire (CHAQ), from a median of 1 at baseline to 0.25 at six months to 0 at 24 months and last assessment (p?0.007). • A significant reduction in pain was observed in treated patients, as measured by the Pediatric Outcomes Data Collection Instrument (PODCI), from a median baseline score of 78 to a median score of 100 at last assessment (p=0.0389). The PODCI is a comfort/pain rating scale, with 100 representing best possible outcome or best health. • Improvements in strength and agility were observed for treated patients as measured by the shuttle run, one-legged hop test and standing long jump, three components of the BOT-2. Median time to complete a 50 foot shuttle run improved from 22 seconds at baseline to 9 seconds at last assessment (p<0.0001). The median number of one-legged stationary hops completed in 15 seconds improved from 0 at baseline to 21 hops at last assessment (p=0.0001). The median distance jumped via a standing long jump improved from 11 inches at baseline to 46 inches at 36 months (p<0.0001). • Improvement in growth, as measured by height Z-score, was observed in treated patients, from a median of -1.26 at baseline to a median of -0.72 at last assessment (p=0.0027). Asfotase alfa was well-tolerated in the study. The most common AEs were mild or moderate injection site reactions. There were no deaths, serious AEs or withdrawals due to AEs over the three years of treatment in this study. Twelve patients tested positive for anti-asfotase antibodies, two of whom had neutralizing antibodies with no apparent effect on efficacy or safety.
• These new analysis and data presented at ASBMR Meeting shows that patients with HPP at high risk of death treated with asfotase alfa had overall survival of 89% versus 27 % for untreated matched historical controls. Patients receiving asfotase alfa also had significantly improved ventilator-free survival compared to historial controls. Improvements in physical function were also observed in new data from infant and juveil phase 2 extension studies presented at  ASBMR.
• Alexion initiated the rolling submission of a Biologics License Application (BLA) for asfotase alfa as a treatment for patients with HPP in April 2014. In July 2014, the Marketing Authorization Application (MAA) for asfotase alfa was validated and granted accelerated assessment by the European Medicines Agency (EMA).

 

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