Clinical Trials

Date: 2015-03-07

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at ENDO 2015

Company: Alexion Pharmaceuticals (USA - CT)

Product: asfotase alfa

Action mechanism:

• enzyme replacement therapy. Asfotase alfa is an investigational, highly innovative, first-in-class enzyme replacement therapy. Asfotase alfa is designed to address the underlying cause of HPP by aiming to restore the genetically defective metabolic process, thereby preventing or reversing the severe and potentially life-threatening complications of life-long dysregulated mineral metabolism.
• In 2013, the FDA granted Breakthrough Therapy designation for asfotase alfa. In 2014, Alexion completed regulatory filings in the U.S., Europe and Japan for asfotase alfa for the treatment of HPP.

Disease: hypophosphatasia

Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases

Country:

Trial details:

Latest news:

• • On March 7, 2015, Alexion Pharmaceuticals announced that researchers presented new data from a retrospective, multinational natural history study of children (symptom onset ?6 months to <18 years) with hypophosphatasia (HPP). In this study, which included 32 patients with juvenile-onset HPP, children with HPP had a substantial disease burden, particularly with regard to musculoskeletal abnormalities and growth deficiencies. The children from this cohort experienced HPP-related skeletal problems, other disease complications and morbidity that persisted despite standard efforts to control symptoms. These data were presented in a late-breaking oral session at the Endocrine Society’s 97th Annual Meeting and Expo (ENDO) in San Diego.
• A Retrospective, Multi-National, Non-Interventional, Natural History Study of the Childhood Form of Hypophosphatasia (Abstract LB-OR01-4): In an oral session, Michael Whyte, M.D., Medical-Scientific Director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospital for Children in St. Louis, presented new results from the first retrospective, multinational, non-interventional natural history study of children (ages ?6 months to <18 years at the onset of symptoms) with HPP. Dr. Whyte reported that children with HPP can have substantial morbidity, including HPP-related skeletal disease that persists throughout childhood in to early adolescence. In this study, investigators reviewed the medical charts of 32 juvenile patients with HPP, all of whom had HPP-related skeletal abnormalities at baseline, to characterize the natural history of skeletal disease and patient growth over the study period. Primary outcome measures were change in bone health, as measured by the Radiographic Global Impression of Change (RGI-C) scale, and change in height Z-score, between 5 and 15 years of age.
• Dr. Whyte reported that: Patients in the cohort manifested a wide range of HPP-related complications, including bowed long bones (59%), gait disturbance (or an abnormal way of walking, 59%), joint pain (53%), bone pain (50%), muscle weakness that limited daily activities (47%), muscle pain (38%) and fractures (34%).
• Eighty-eight percent of patients required surgical or medical intervention, 63% required medications for HPP symptoms and 13% required wheelchairs and/or walking aids. No significant change in RGI-C score was observed between the first and last assessment, as measured over a median of 4.25 years (+0.33; p=0.08). No significant change in height Z-score was observed from first to last assessment (p=0.63). Median height Z-score was -0.9 at both baseline and last assessment, indicating less than average relative to peers. There also was no significant change in weight Z-score. “This retrospective natural history study underscores the persistent nature of HPP in children and adolescents. These findings enhance our understanding of the clinical course of HPP with currently available supportive care and further illustrate the important impact this disease can have on patients,” said Dr. Whyte.
• Gait Assessment in Children with Childhood Hypophosphatasia: Impairments in Muscle Strength and Physical Function (Abstract LBS-039): Dawn Phillips, Ph.D., Physical Therapist and Functional Outcomes Specialist, UNC Division of Physical Therapy, Chapel Hill, N.C., presented results from a clinical gait assessment in a subset of children (n=6) enrolled in the juvenile natural history study. The analysis was based on video recordings over a median of 4.1 years. Researchers assessed gait performance, or walking ability, using the 12-point Performance-Oriented Mobility Assessment (POMA-G), modified to provide improved sensitivity for HPP-related impairments (MPOMA-G) (12=no impairments; lower scores indicate greater impairment). A physical therapy descriptor checklist and chart provided further information on physical function. At first assessment, median MPOMA-G score was 6.0, representing substantial gait defects, and all patients displayed trunk sway (movements of the trunk or arms to maintain balance). At last assessment, all patients had persistent gait impairments, with a median MPOMA-G score of 7.5. No consistent pattern of change in any MPOMA-G component was observed. In addition, 66% (4/6) of patients were unable to achieve a “period of flight” at last assessment, indicating inability to run; all patients (6/6) required self-support with a hand to transition from the floor to standing; and all patients (6/6) reported limitation of activity due to pain/fatigue.
• Significantly Improved Muscle Strength, Running Speed, and Agility in Children with Hypophosphatasia Treated with Asfotase Alfa (Abstract OR29-4): In an oral session, researchers reported results from the extension phase of a multinational, open-label Phase 2 study in children with HPP (N=12, ages 5-12 at study entry) who were treated with asfotase alfa for at least three years. Select findings from this study were presented at the American Society for Bone and Mineral Research (ASBMR) meeting in September 2014, including improvements in certain measures of physical function and agility, as measured by the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2); disability, as measured by the Child Health Assessment Questionnaire (CHAQ); and pain, as measured by the Pediatric Outcomes Data Collection Instrument (PODCI). New data presented at ENDO showed that:
• Hip and knee strength, as measured by Hand Held Dynamometry (HDD) (including hip extension and flexion, and knee extension and flexion), improved over time and was sustained at last assessment (P<0.05). Physical function, as measured by the BOT-2 Strength subtest (including standing long jump, push-ups, sit-ups, wall sit and V-ups), improved rapidly from a median scaled score of 4 at baseline to a median score of 15 at last assessment (P<0.0001), and was within the normal range for healthy peers by treatment Month 6. Running speed and agility, as measured by the BOT-2 Running Speed and Agility subtest (including 50 ft. shuttle run, sideways steps over balance beam, and 1- and 2-legged hops), improved rapidly from a median scaled score of 4 at baseline to a score of 12 at last assessment (P<0.0001). The most common AEs were injection site reactions (none serious or severe).There were no deaths, other serious AEs or withdrawals due to AEs.
• Improved Activities of Daily Living and Physical Function, with Decreased Pain, in Children with Hypophosphatasia Treated for Three Years with Asfotase Alfa: Results from the Childhood Health Assessment Questionnaire and the Pediatric Outcomes Data Collection Instrument (Abstract FRI-224):  In a poster session at ENDO, researchers presented new data from the extension phase of the same multinational, open-label Phase 2 study in children with HPP. These data showed that:
• Patients had a median pain score of 20.0 at baseline, as measured by the CHAQ discomfort index, which rapidly decreased to 0.0 at 6 months (P=0.082). Median scores were sustained at 0 through last assessment (p<0.05) at three years, indicating that most patients remained pain-free. Functional status, as measured by the parent-reported PODCI, improved across several key categories: Median Global Functioning scores improved from 27 at baseline to 49 at 6 months (P=0.003) and continued to improve to 52.5 (P<0.001), within healthy range, by last assessment Median Sports/Physical Functioning scores improved from 20 at baseline to 43.5 at 6 months (P=0.0002), within healthy range, and continued to improve to 47.5 at last assessment (P=0.0002) Median Transfer and Basic Mobility scores improved from 37 at baseline to 52 at 6 months (P=0.033), within healthy range, and sustained at 52 through last assessment (P=0.008) The most common AEs were injection site reactions (none serious or severe).There were no deaths, serious adverse events (AEs) or withdrawals due to AEs.
• Burden of Disease in Adult Patients with Hypophosphatasia: Results from Patient-Reported Outcome Surveys (Abstract FRI-240): In a poster session, researchers reported findings from the Hypophosphatasia Impact Patient Survey (HIPS) and the Hypophosphatasia Outcomes Study Telephone interview (HOST), which were completed by 125 adult patients (?18 years old) with a mean age of 45 years.5 Patients were classified into two subgroups based on age at onset: <18 years (pediatric-onset, n=84) and ?18 years (adult-onset, n=34; onset information was unknown in 7 patients). This was the first study to describe patient-reported burden of disease and morbidity in patients with HPP. Key findings from the study are as follows:
• Pain was prevalent and reported in almost all patients (119/125, or 95%); 90% (113/125) reported that pain was recent Seventy-six percent (68/89, HIPS only) reported bone pain severe enough to limit activity The majority of patients (108/125, or 86%) reported experiencing at least one fracture; the average number of fractures sustained was 12.9 (13.7 for patients with pediatric-onset disease and 10.3 for patients with adult-onset disease) Commonly reported clinical manifestations included muscle weakness (62% overall, 64% for pediatric-onset, and 65% for adult-onset) and unusual gait (52% overall, 61% for pediatric-onset, and 36% for adult-onset) More than half of patients had used an assistive device for mobility at some time (60% overall and 62% each for pediatric-onset and adult-onset); at the time of the survey, 34% of patients overall reported using an assistive device to walk and 22% overall required a wheelchair Researchers concluded that, in this cohort of self-reported information, HPP results in a high burden of disease in adulthood regardless of age of onset.

Is general: Yes