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

Phase 4

Not yet recruiting

• Conditions: Hypophosphatasia
• Interventions: Drug: methotrexate; Drug: rituximab; Drug: bortezomib; Drug: IVIg; Drug: Folic Acid

• Registration Number: NCT06015750
• Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary

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).

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 Timeline

• Study First Submitted: 2023-08-23
• Study First Submitted QC: 2023-08-23
• Study First Posted: 2023-08-29
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-17
• Last Update Posted: 2025-02-18
• Study Start: 2025-07-02
• Primary Completion: 2029-02-14
• Study Completion: 2029-02-14

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 8

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Pediatric participants with HPP	methotrexate	Pediatric participants who have been receiving asfotase alfa treatment for their HPP, and who demonstrate immune-mediated LoE.
Pediatric participants with HPP	rituximab	Pediatric participants who have been receiving asfotase alfa treatment for their HPP, and who demonstrate immune-mediated LoE.
Pediatric participants with HPP	bortezomib	Pediatric participants who have been receiving asfotase alfa treatment for their HPP, and who demonstrate immune-mediated LoE.
Pediatric participants with HPP	IVIg	Pediatric participants who have been receiving asfotase alfa treatment for their HPP, and who demonstrate immune-mediated LoE.
Pediatric participants with HPP	Folic Acid	Pediatric participants who have been receiving asfotase alfa treatment for their HPP, and who demonstrate immune-mediated LoE.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Achieve Immunosuppressive Therapy (IST) Complete Response at Week 100	Week 100

Secondary Outcome Measures

Name	Time	Method
ADA and NAb Titer Levels	Baseline Through Week 100
Number Participants with Antidrug Antibodies (ADAs) and Neutralizing Antibodies (NAbs)	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

Trial Locations

Locations (1)

Research Site; 🇬🇧 Manchester, United Kingdom