Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia (RESTORE)

An Interventional, Prospective Open-Label Study of Immunosuppressive Therapies to Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia (RESTORE)

The primary objective of this study is to evaluate the effect of immunosuppressive therapy (IST) in participants treated with asfotase alfa who demonstrate immune-mediated loss of effectiveness (LoE).

Study Overview

• Status: Withdrawn
• Conditions: Hypophosphatasia
• Intervention / Treatment: Drug: methotrexate; Drug: rituximab; Drug: bortezomib; Drug: IVIg; Drug: Folic Acid

Detailed Description

The administration of biological drugs to patients, especially for chronic conditions, carries a risk of eliciting anti-drug antibodies. Neutralizing antibodies can neutralize the clinical benefit of the agent. In postmarketing safety surveillance, some patients treated with asfotase alfa demonstrated an initial response, but subsequently recurrence and progression of disease. Consequently, the FDA requested a study to assess a potential serious risk of immune-mediated loss of effectiveness.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Le Kremlin-Bicêtre, France, 94270
    • Research Site
• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Reoccurrence or worsening of rickets for at least the past 3 months in participants who showed an initial efficacy response to asfotase alfa after at least 6 months of continuous treatment and currently receiving asfotase alfa. RSS will be used to determine severity at Baseline.
• Presence of ADAs, with or without NAbs, irrespective of their titers.
• Confirmation by the TMB that both the clinical evidence and immunogenicity-mediated association noted above are present.
• Female participants of childbearing potential and male participants with partners of childbearing potential must follow protocol-specified contraception guidance as described in Section 10.5.
• Participant, or participant's legal guardian, is capable of signing informed consent or assent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the informed consent or assent form and in this protocol.

Exclusion Criteria:

• Known history of human immunodeficiency virus (HIV) infection (evidenced by HIV type 1 or type 2 [HIV 1, HIV 2] antibody) or hepatitis B or C viral infection.
• Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to Screening.
• Inability of the participant, or the participant's legal guardian, to provide informed consent.
• Pregnant, breastfeeding, or intending to conceive during the course of the study.
• Inability to travel to the clinic for specified visits during the Treatment Period caused by disease per se or logistics (does not apply to external travel restrictions).
• The participant is at risk of reactivation or has an active significant viral infection such as hepatitis B, cytomegalovirus, herpes simplex, human polyomavirus (also known as John Cunningham [JC] virus), parvovirus, or Epstein Barr virus.
• The participant is at risk of reactivation of tuberculosis or has regular contact (eg, in the household) with individuals who are being actively treated for tuberculosis.
• The participant has had or is required to have any live vaccination within 1 month prior to enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Pediatric participants with HPP; Pediatric participants who have been receiving asfotase alfa treatment for their HPP, and who demonstrate immune-mediated LoE.

Drug: methotrexate; Methotrexate will be administered SC or orally weekly for 104 weeks.; Drug: rituximab; Rituximab will be administered intravenously (IV) continuously weekly, for up to 74 weeks.; Drug: bortezomib; Bortezomib will be administered via IV bolus or SC, as needed.; Drug: IVIg; IVIg will be administered via IV monthly through initial 74 weeks.; Drug: Folic Acid; Folic acid will be given orally as long as methotrexate is being dosed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants Who Achieve Immunosuppressive Therapy (IST) Complete Response at Week 100	Week 100

Secondary Outcome Measures

Outcome Measure	Time Frame
Number Participants with Antidrug Antibodies (ADAs) and Neutralizing Antibodies (NAbs)	Baseline Through Week 100
ADA and NAb Titer Levels	Baseline Through Week 100
Serum Concentration of Asofatase Alfa (Measured as Enzyme Activity)	Baseline Through Week 100
Plasma Concentration of Pyridoxal-5ˈ-Phosphate (PLP)	Baseline Through Week 100
Plasma Concentration of Inorganic Pyrophosphates (PPi)	Baseline Through Week 100
Number of Participants with Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events	Baseline Through Week 104

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): July 29, 2026
• Primary Completion (Estimated): March 13, 2030
• Study Completion (Estimated): March 13, 2030

Study Registration Dates

• First Submitted: August 23, 2023
• First Submitted That Met QC Criteria: August 23, 2023
• First Posted (Actual): August 29, 2023

Study Record Updates

• Last Update Posted (Actual): December 18, 2025
• Last Update Submitted That Met QC Criteria: December 10, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Hypophosphatasia; HPP; Asfotase alfa; Strensiq
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Metal Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hypophosphatasia; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Pterins; Pteridines; Aminopterin; Immunoglobulin Isotypes; Immunoglobulin G; Antibodies, Monoclonal, Murine-Derived; Boronic Acids; Acids, Noncarboxylic; Acids; Boron Compounds; Pyrazines; Rituximab; Bortezomib; Methotrexate; Folic Acid; Immunoglobulins, Intravenous
• Other Study ID Numbers: D8400C00001; 2022-502793-17 (EudraCT Number); AA-HPP-407 (Other Identifier: Alexion)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR, and plain language summaries.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No