Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)

NCT01163149 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: ENB-009-10
• Study Type: interventional
• Target: 19
• Locations: 2 countries
• Sites: 3

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 two doses of the study drug called asfotase alfa as compared to a control group to see effects on adolescents and adults with HPP.

Conditions

Hypophosphatasia

Keywords

Hypophosphatasia; HPP; Bone Disease; Soft Bones; Low Alkaline Phosphatase; genetic metabolic disorder; alkaline phosphatase; tissue-specific alkaline phosphatase (TNSALP); rickets; osteomalacia

Outcome Measures

Primary Outcomes (3)

• Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP)

  Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP)

  Baseline, Week 24

• Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi)

  Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma inorganic pyrophosphate (PPi)

  Baseline, Week 24

• Safety and Tolerability of Asfotase Alfa

  The safety and tolerability of daily subcutaneous (SC) injections of asfotase alfa was assessed by routine monitoring of patients for treatment-emergent adverse events (TEAEs) and injection-associated reactions (IARs).

  Up to 288 weeks exposure to asfotase alfa

Secondary Outcomes (6)

• Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA)

  Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.

• Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA)

  Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.

• Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT)

  Baseline, Week 24 (primary treatment period) and up to 288 weeks of asfotase alfa exposure

• Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume

  Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).

• Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Thickness

  Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).

Study Arms (3)

Cohort 1

EXPERIMENTAL

Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)

Drug: asfotase alfa

Cohort 2

EXPERIMENTAL

Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)

Drug: asfotase alfa

Concurrent Control

NO INTERVENTION

Following completion of the Week 24 visit, all patients (including those randomized to the concurrent control cohort) may be eligible to participate in an open-label extension treatment period. In this extension period, all patients will be treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects will receive 1 mg/kg/day 6 days/week for an additional 48 weeks or until regulatory approval of the drug.

Interventions

asfotase alfa DRUG

Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (total of 2.1 mg/kg/week)

Cohort 1

Eligibility Criteria

• Age: 13 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients or their legal representative(s) must provide written informed consent prior to undergoing any study-related procedures
• Patients must be ≥ 13 and ≤ 65 years of age at the time of study enrollment
• Female patients of childbearing potential and sexually mature males must agree to use a medically acceptable form of birth control; for the purposes of this study, females are considered of non-childbearing potential if they are surgically sterile (i.e., have undergone a total hysterectomy, bilateral salpingo-oophorectomy or tubal ligation) or are post-menopausal, defined as having complete cessation of menstruation for at least 1 year after 45 years of age
• Patients must have a pre-established clinical diagnosis of HPP as indicated by:
• Serum alkaline phosphatase (ALP) below the age-adjusted normal range
• Plasma PLP at least twice the upper limit of normal (no vitamin B6 administered for at least 1 week prior to determination)
• Evidence of osteopenia or osteomalacia on skeletal radiographs
• Patients must have osteomalacia on bone biopsy, characterized by an MLT z-score of +2 or more (results from ENB-001-08 may be used)
• Patients must be willing to comply with study procedures and the visit schedule

You may not qualify if:

• Women who are pregnant or lactating
• History of sensitivity to tetracycline
• Serum calcium or phosphate levels below the normal range
• Serum 25(OH) vitamin D below 20 ng/mL
• Serum creatinine or parathyroid hormone (PTH) levels above the upper limit of normal
• Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities
• Orthopedic surgery within 12 months prior to study entry that may interfere with the ability to perform functional assessments for the study
• Prior treatment with bisphosphonates within 2 years of study entry for any length of time or for more than 2 years at any time point; for patients with prior bisphosphonate use that is allowed, the bone resorption markers serum C-telopeptide and urine N-telopeptide or urine deoxypyridinoline must also be within the normal range or elevated to be eligible for study participation
• Treatment with PTH within 6 months prior to the start of asfotase alfa administration
• Participation in an interventional or investigational drug study within 30 days prior to study participation

Sponsors & Collaborators

• Alexion Pharmaceuticals, Inc.: lead

Study Sites (3)

Shriner's Hospital for Children

St Louis, Missouri, 63131, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Health Sciences Centre Winnipeg, University of Manitoba

Winnipeg, Manitoba, R3A 1S1, Canada

Location

Related Publications (3)

• Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):777-87. doi: 10.1359/jbmr.071213.

  PMID: 18086009 BACKGROUND

• Simmons JH, Rush ET, Petryk A, Zhou S, Martos-Moreno GA. Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data. Bone. 2020 Aug;137:115413. doi: 10.1016/j.bone.2020.115413. Epub 2020 May 14.

  PMID: 32417537 DERIVED

• Gospe SM 3rd, Santiago-Turla C, DeArmey SM, Cummings TJ, Kishnani PS, Bhatti MT. Ectopic Ocular Surface Calcification in Patients With Hypophosphatasia Treated With Asfotase Alfa. Cornea. 2019 Jul;38(7):896-900. doi: 10.1097/ICO.0000000000001947.

  PMID: 30969260 DERIVED

Related Links

• HPP support group
• US Hypophosphatasia Group (Soft Bones)
• Hypophosphatasia Website
• Hypophosphatasia Website for Healthcare Providers

MeSH Terms

Conditions

Hypophosphatasia; Bone Diseases; Rickets; Osteomalacia

Interventions

asfotase alfa

Condition Hierarchy (Ancestors)

Metal Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases, Metabolic; Calcium Metabolism Disorders; Vitamin D Deficiency; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders

Results Point of Contact

• Title: Director of Clinical Trials
• Organization: Alexion Pharmaceuticals, Inc.

ClinicalTrials@alexion.com

475-230-2596

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 24, 2010
• First Posted: July 15, 2010
• Study Start: June 1, 2010
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: March 13, 2019
• Results First Posted: September 18, 2017

Record last verified: 2019-03

Locations

US (2); CA (1)