Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency

Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal Trial With Tadekinig Alfa (r-hIL-18BP) in Patients With IL-18 Driven Monogenic Autoinflammatory Conditions: NLRC4 Mutation and XIAP Deficiency

This is a Phase 3 study to assess the safety and efficacy of Tadekinig alfa in patients with monogenic, interleukin-18 (IL 18) driven autoinflammation due to Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruiting domain (CARD domain) containing 4 (NLRC4) - Macrophage activation syndrome (MAS) mutation (NLRC4-MAS mutation) or X-linked inhibitor of apoptosis (XIAP) deficiency. Because of the likelihood for pathogenic IL-18 in certain monogenic diseases, patients known to harbor deleterious mutations in NLRC4-MAS or XIAP and who have a history of ongoing inflammation will be enrolled if they have ferritin ≥ 500 ng/mL or persistent C reactive protein (CRP) elevation ≥ 2 times the upper limit of normal (ULN) and the patients should have a Modified Autoinflammatory Disease Activity Index (mAIDAI) ≥ 4.

Study Overview

• Status: Completed
• Conditions: NLRC4-MAS; XIAP Deficiency
• Intervention / Treatment: Drug: Tadekinig alfa; Other: 0.9% sodium chloride

Detailed Description

The study is designed with single-arm, open-label phase (SAOL) of Tadekinig alfa treatment duration for 18-week followed by an up to 16-week Randomized Withdrawal (RW) period for efficacy and safety evaluation, with no interruption between the two phases of treatment. The screening period will occur before the SAOL phase and before the first dose of Investigational Medicinal Product (IMP)

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, ON M5G 1X8
      • The Hospital for Sick Children
  • Providence
    • Montréal, Providence, Canada, QC H3T 1C5
      • CHU Sainte-Justine
• Germany
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
      • Universitätsklinikum Freiburg, Centrum für Chronische Immundefizienz (CCI) - Paediatric Unit
• United States
  • California
    • La Jolla, California, United States, 92056
      • UCSD _ Department of Pediatrics / Rady Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta at Egleston
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital _ Baylor College of Medicine

Participation Criteria

Eligibility Criteria

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

Description

INCLUSION CRITERIA

1. Patients with genetic diagnosis of NLRC4-MAS mutation or XIAP deficiency (caused by BIRC4 gene mutation) as confirmed by analysis performed at the central genetics laboratory. If possible, flow cytometry assay will be performed in parallel to confirm diagnosis of XIAP deficiency. (Note: Previous flow cytometry assay results will be permitted for confirmation of XIAP deficiency diagnosis.)
2. Patients with XIAP deficiency and a previous bone marrow transplantation are allowed, if they show evidence of primary or secondary graft failure, or failure to achieve phenotypic correction with evidence of XIAP-related disease recurrence or clinically significant mixed chimerism.
3. Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥4
4. Patients receiving corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or disease modifying anti-rheumatic drugs (DMARDs), and/or IL-1 blockade with insufficient response to treatment upon enrollment are allowed into the study. Patients not receiving any of these treatments before start of therapy are also allowed.
5. Women of childbearing potential with negative urine pregnancy test (UPT) at all visits (if UPT is positive, a blood test for human chorionic gonadotropin (hCG) to be performed) and who agree to follow highly effective birth control recommendations during the study and until 1 month after the end of the treatment. Birth control methods considered highly effective are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence. In each case of delayed menstrual period (over one month between menstruations, confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of childbearing potential with infrequent or irregular menstrual cycles. A post-study contraception duration of 4 weeks is recommended taking into account the median half-life of Tadekinig alfa of almost 40h and 5 half-lives representing a duration of 200 hours.

EXCLUSION CRITERIA

1. Patients with life-threatening co-morbidities not associated with the underlying NLRC4-mutation or XIAP deficiency
2. Positive test for or prior history of HIV, Hepatitis B or Hepatitis C (serology)
3. Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy
4. Presence of life threatening infections
5. Oncologic causes of symptoms; current or previous history of malignancy
6. Presence of CNS manifestations (i.e. seizures, altered mental status, signs of increased intracranial pressure, chronic papilledema, loss of vision, other sensorineural deficiencies, etc.)
7. Patients suffering from biallelic mutations in any of the following genes: PRF1/Perforin, UNC13D/Munc 13-4, STX11/Syntaxin11, STXB2/Munc 18-2, RAB27A/Rab27a (Griscelli syndrome type 2), LYST (Chediak-Higashi syndrome), AP3B1, ADTB3A, HPS2 mutations (Hermansky-Pudlak syndrome 2) and X-linked lymphoproliferative syndrome (XLP)-1 with SH2D1A mutation
8. Patients who are pregnant or nursing, women of childbearing potential who are unwilling to use highly effective birth control methods (see definition in Inclusion Criteria above) through 4 weeks after the end of their participation in the study
9. Concomitant use of immunosuppression therapies excluded by the protocol. Note: NSAIDs, glucocorticoids, cyclosporine, tacrolimus, and IL-1 inhibitors (anakinra, canakinumab, or rilonacept, or others) are allowed
10. Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent
11. Hypersensitivity to the active substance or one of the excipients of the investigational product

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tadekinig alfa; Patients that showed response to treatment in the SAOL phase will receive Tadekinig alfa for up to 16 weeks.	Drug: Tadekinig alfa; Tadekinig alfa is a soluble glycoprotein of 164 amino acids produced from Chinese Hamster Ovary cell line. Tadekinig alfa is supplied as a colorless to slightly yellow, sterile solution for injection in glass vials containing sodium chloride, and 0.02M sodium phosphate buffer as excipients. It is available in a concentration of 20mg/0.5mL.; Other Names: IL-18BP; r-hIL-18BP
Placebo Comparator: 0.9% sodium chloride; Patients that showed response to treatment in the SAOL phase will receive placebo comparator for up to 16 weeks.	Other: 0.9% sodium chloride; To ensure that the treatment remains blinded for the entire study period, the placebo solutions will be supplied in identical vials and similar labelling as the active drug and will be indistinguishable in terms of their texture, color, and smell.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevention of Flares	The primary outcome measure is the time to first occurrence of disease reactivation during the 16-week RW phase. Method of assessment: Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage.	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Response	Best response to therapy during the SAOL phase including either complete response, partial response or disease improvement. Method of assessment: Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage.	18 weeks
Duration of Response During the SAOL Phase (Until End of Phase or Disease Reactivation)	Duration of response to therapy during the SAOL phase is assessed for patients having achieved a complete or partial response to therapy during the SAOL phase. It is defined as the time from first evaluation of partial or complete response until the time of subsequent disease reactivation or end of SAOL phase, whichever occurs first. Of the 11 patients achieving partial or complete response during the SAOL phase, 8 maintained treatment response until the end of the SAOL phase. 2 of the 11 patients had a temporary disease reactivation during the protocol mandated steroid weaning in the SAOL phase; 1 of the 11 patients was withdrawn from blinded treatment following a disease reactivation.	The actual mean treatment duration in the SAOL phase was 17.6 weeks (minimum / maximum 5.9 / 22.1 weeks).
Change From Baseline in mAIDAI Total Score in the SAOL Phase	The mAIDAI (modified autoinflammatory disease activitiy index) is an assessment of global disease activity that measures 14 different components for disease as either absent (0 points) or present (2 points for Uveitis 3+/4+ and 1 point for all other symptoms) at each visit. The mAIDAI total score is the sum of the points assigned across all components and ranges from 0 to 15, with a higher score indicating more severe disease activity.	18 weeks
Change From Baseline in Serum Ferritin	Laboratory measure	34 weeks
Change From Baseline in Serum CRP	Laboratory measure	34 weeks
Resolution of Fevers, Hepato/Splenomegaly and Skin Rash	Clinical assessments if present at Baseline; number displays percentage of patients with resolution of individual disease component at Week 18 or early termination visit based on the number of patients with a baseline assessment for the component of interest.	18 weeks
Improvement in Laboratory Markers - AST (SGOT)	Change from Baseline mean value to Week 18 mean value	18 weeks
Improvement in Laboratory Markers - ALT (SGPT)	Change from Baseline mean value to Week 18 mean value	18 weeks
Improvement in Laboratory Markers - Albumin	Change from Baseline mean value to Week 18 mean value	18 weeks
Improvement in Laboratory Markers - Hemoglobin	Change from Baseline mean value to Week 18 mean value	18 weeks
Improvement in Laboratory Markers - Platelets	Change from Baseline mean value to Week 18 mean value	18 weeks
Improvement in Laboratory Markers - Erythrocyte Sedimentation Rate	Change from Baseline mean value to Week 18 mean value	18 weeks
Improvement in Laboratory Markers - Fibrinogen	Change from Baseline mean value to Week 18 mean value	18 weeks
Improvement in Laboratory Markers - D-Dimer	Change from Baseline mean value to Week 18 mean value	18 weeks
Hospital Length of Stay	Length of hospitalisation; emergency room attendance and unscheduled visits for treatment of disease reactivations not included	34 weeks
Change in Physician Global Assessment (PGA)	The PGA is a direct surrogate of how a patient functions and assesses the severity of disease-related (auto-inflammatory) symptoms by selecting an integer score from 0 (no impact on subject; no symptoms) to 10 (no normal activities possible; highest severity of symptoms possible). The outcome lists the change from baseline of treatment phase to end of treatment phase/study in the PGA symptom severity score.	34 weeks
Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase	The individual disease-related symptoms score is the sum of (x) individual symptom scores within domain each ranging from 0 (None) to 5 (Very severe) for: general wellbeing (5), gastrointestinal (7), musculoskeletal (5), skin (2), eye (2), central nervous system (3), and lymphatic (2). Highest values indicate more severe disease-related symptoms within total score range from 0-130.	16 weeks
Immunogenicity Evaluation	Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies	34 weeks (SAOL + RW phases)
Local Tolerability at the Injection Site (as Defined by Number of Participants With Adverse Events of Special Interest)	Adverse events of special interest (AESIs) are defined for this protocol as injection site reactions (including pruritus, erythema, swelling).	34 weeks (SAOL + RW phases)
Disease Reactivation Rate	Disease reactivation rate for individual subjects (number of disease reactivations experienced per week while each subject is on the study treatment during the SAOL phase)	18 weeks
Treatment Failures	Treatment failures (i.e. patients who experience at least one disease reactivation) during the SAOL phase	18 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to Therapy - Key Secondary Efficacy Endpoint	Response to therapy (including complete response and partial response) in the SAOL phase from Week 10 onwards and observed at least at 2 consecutive visits at least 2 weeks apart during the SAOL phase	18 weeks

Collaborators and Investigators

• Sponsor: AB2 Bio Ltd.
• Investigators: Principal Investigator: Ed M Behrens, MD, Children Hospital of Philadelphia

Publications and helpful links

General Publications

• Krei JM, Moller HJ, Larsen JB. The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome - a systematic review. Clin Exp Immunol. 2021 Feb;203(2):174-182. doi: 10.1111/cei.13543. Epub 2020 Nov 23.

Helpful Links

• Sponsor details

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2017
• Primary Completion (Actual): October 31, 2023
• Study Completion (Actual): November 2, 2023

Study Registration Dates

• First Submitted: February 28, 2017
• First Submitted That Met QC Criteria: April 10, 2017
• First Posted (Actual): April 14, 2017

Study Record Updates

• Last Update Posted (Actual): July 2, 2025
• Last Update Submitted That Met QC Criteria: June 13, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Immune System Diseases; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoproliferative Disorders; Genetic Diseases, X-Linked
• Other Study ID Numbers: NLRC4/XIAP.2016.001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: This information will be provided soon

Drug and device information, study documents

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