Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)

Phase 2

Completed

Conditions: Hypophosphatasia

Interventions: Drug: asfotase alfa

Registration Number: NCT01176266

Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary: This clinical trial was conducted to study hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. The purpose of this study was to test the safety and efficacy of a study drug called asfotase alfa (human recombinant tissue non-specific alkaline phosphate fusion protein) to see what effects it has on patients 5 years of age or less with HPP.

Detailed Description: Asfotase alfa was formerly referred to as ENB-0040

Hypophosphatasia (HPP) is a life-threatening, genetic, and ultra-rare metabolic disease characterized by defective bone mineralization and impaired phosphate and calcium regulation that can lead to progressive damage to multiple vital organs, including destruction and deformity of bones, profound muscle weakness, seizures, impaired renal function, and respiratory failure. There are limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 69

Inclusion Criteria

Patients must meet all of the following criteria for enrollment in this study:

Parent or legal guardian(s) must provide written informed consent prior to any study procedures being performed and must be willing to comply with all study-required procedures. Where appropriate and required by local regulations, patient assent should also be provided prior to any study procedures being performed.
Documented diagnosis of HPP as indicated by:
1. Total serum alkaline phosphatase (ALP) below the lower limit of normal for age NOTE: Historical values for ALP may be used to determine patient eligibility.
2. Plasma pyridoxal-5'-phosphate (PLP) above the upper limit of normal (unless patient is receiving pyridoxine for seizures) NOTE: Historical values for PLP may be used to determine patient eligibility.
3. Radiographic evidence of HPP at screening, characterized by:
  - Flared and frayed metaphyses, and
  - Severe, generalized osteopenia, and
  - Widened growth plates, and
  - Areas of radiolucency or sclerosis
4. Two or more of the following HPP-related findings:
  - History or presence of: i) Nontraumatic post-natal fracture or ii) Delayed fracture healing
  - Nephrocalcinosis or history of elevated serum calcium
  - Functional craniosynostosis
  - Respiratory compromise or rachitic chest deformity
  - Vitamin B6-responsive seizures
  - Failure to thrive
Onset of symptoms prior to 6 months of age
Chronological age or adjusted age for premature infants born ≤ 37 weeks gestation of ≤ 5 years
Otherwise medically stable in the opinion of the Investigator and/or Sponsor

Exclusion criteria:

Patients will be excluded from enrollment in this study if they meet any of the following exclusion criteria:

Clinically significant disease that precludes study participation, in the opinion of the Investigator and/or Sponsor
Serum calcium or phosphate levels below the normal range
Current evidence of treatable form of rickets
Prior treatment with bisphosphonates
Treatment with an investigational drug within 1 month prior to the start of asfotase alfa treatment
Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)
Intolerance to the investigational product (IP) or any of its excipients
Previous participation in the same study
Family relative of the Investigator

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Asfotase alfa	asfotase alfa	A total of 6 mg/kg/week of asfotase alfa administered by SC injection (either 1 mg/kg asfotase alfa 6 times per week, or 2 mg/kg asfotase alfa 3 times per week)

Primary Outcome Measures

Name	Time	Method
Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)	From Baseline to Week 24	The effect of asfotase alfa treatment on skeletal manifestations of HPP (i.e., change in rickets severity) was measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale. Skeletal radiographs obtained at Week 24 were compared with skeletal radiographs obtained before initiation of treatment. The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets).
Safety and Tolerability of Repeated Subcutaneous (SC) Injections of Asfotase Alfa	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients was assessed by the number of patients with 1 or more treatment-emergent adverse event.

Secondary Outcome Measures

Name	Time	Method
Effect of Asfotase Alfa Treatment on Respiratory Function	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	Effect of asfotase alfa treatment on respiratory function as measured by the shift in proportion of patients requiring respiratory support at their last assessment compared with Baseline.
Effect of Asfotase Alfa Treatment on Skeletal Manifestations of Hypophosphatasia (HPP)	Up to 72 Months or regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	The effect of asfotase alfa treatment on skeletal manifestations of HPP (i.e., change in rickets severity) was measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale. Skeletal radiographs obtained at the patient's last assessment were compared with skeletal radiographs obtained before initiation of treatment. The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets).
Effect of Asfotase Alfa Treatment on Physical Growth - Weight Z-scores Change From Baseline to Last Obtained Value	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	Effect of asfotase alfa treatment on physical growth as measured by change from Baseline to last assessment for each patient in weight Z-scores
Effect of Asfotase Alfa Treatment on Ventilator-free Survival (Week 312)	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	For patients who were not on respiratory support at the time of enrollment, the Kaplan-Meier estimate of ventilator-free survival at the end of the study
Pharmacokinetic (PK) Properties of Asfotase Alfa (AUCt)	PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose	The PK properties (AUCt) of asfotase alfa
Effect of Asfotase Alfa Treatment on Physical Growth - Length/Height Z-scores Change From Baseline to Last Obtained Value	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	Effect of asfotase alfa treatment on physical growth as measured by change from Baseline to last assessment for each patient in length/height Z-scores
Effect of Asfotase Alfa on Biomarkers - Plasma Inorganic Pyrophosphate (PPi) Change From Baseline to Last Obtained Value	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	Effect of asfotase alfa on PPi as measured by change from Baseline to last assessment for each patient
Effect of Asfotase Alfa Treatment on Tooth Loss	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	Effect of asfotase alfa treatment on tooth loss assessed by the proportion of patients who experienced tooth loss during the study
Effect of Asfotase Alfa on Biomarkers - Plasma Pyridoxal-5' Phosphate (PLP) Change From Baseline to Last Obtained Value	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	Effect of asfotase alfa on PLP as measured by change from Baseline to last assessment for each patient
Effect of Asfotase Alfa on Serum Parathyroid Hormone (PTH) - Change From Baseline to Last Obtained Value	Up to 72 months or until regulatory approval in the country of residence. Patients received study drug for a median duration of 829.0 days, with a range from 6 to 2116 days (ie, from 0.9 week to 5.8 years).	Effect of asfotase alfa on serum PTH as measured by change from Baseline to last assessment for each patient
Pharmacokinetic (PK) Properties of Asfotase Alfa (Tlast)	PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose	The PK properties (tlast) of asfotase alfa
Pharmacokinetic (PK) Properties of Asfotase Alfa (Cmax)	PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose	The PK properties (Cmax) of asfotase alfa
Pharmacokinetic (PK) Properties of Asfotase Alfa (Tmax)	PK parameters were calculated using Week 6 study visit data. Week 6 study visit blood samples for PK testing were drawn pre-dose and 6, 12, 24, 32, and 48 hours post dose	The PK properties (tmax) of asfotase alfa

Trial Locations

Locations (23): Chu de Toulouse
🇫🇷
Toulouse, France
Federal State Budgetary Institution
🇷🇺
Moscow, Russian Federation
Universitätskinderklinikum Würzburg
🇩🇪
Würzburg, Germany
Tokyo Medical University Hospital
🇯🇵
Shinjuku, Tokyo, Japan
Hospital Infantil Universitario Nino Jesus
🇪🇸
Madrid, Spain
Children's Hospital & Research Center Oakland
🇺🇸
Oakland, California, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Lady Cilento Children's Hospital
🇦🇺
South Brisbane, Queensland, Australia
Sheffield Children'S Hospital
🇬🇧
Sheffield, United Kingdom
Necker Hospital
🇫🇷
Paris, France
Fukuoka Higashi Medical Hospital
🇯🇵
Koga, Fukuoka, Japan
St. Marianna University School of Medicine, Yokohayama City Seibu Hospital
🇯🇵
Yokohama, Kanagawa, Japan
Birmingham Children's Hospital
🇬🇧
Birmingham, United Kingdom
Royal Manchester Children'S Hospital
🇬🇧
Manchester, United Kingdom
Health Sciences Centre Winnipeg, University of Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
Uludag University
🇹🇷
Bursa, Turkey
Ospedale Pediatrico Bambino Gesù
🇮🇹
Roma, Italy
Istituto Giannina Gaslini
🇮🇹
Genova, Italy
Ishikawa Prefectural Hospital
🇯🇵
Kanazawa, Ishikawa, Japan
King Faisal Specialist Hospital and Research Center
🇸🇦
Riyadh, Saudi Arabia
Saitama Municipal Hospital
🇯🇵
Saitama, Japan
Royal Children'S Hospital Melbourne
🇦🇺
Parkville, Victoria, Australia