Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency

NCT03113760 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: NLRC4/XIAP.2016.001
• Study Type: interventional
• Target: 15
• Locations: 3 countries
• Sites: 9

Brief Summary

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.

Conditions

NLRC4-MAS; XIAP Deficiency

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (21)

• Best Response

  18 weeks

• Duration of Response During the SAOL Phase (Until End of Phase or 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

  18 weeks

• Change From Baseline in Serum Ferritin

  34 weeks

• Change From Baseline in Serum CRP

  34 weeks

Other Outcomes (1)

• Response to Therapy - Key Secondary Efficacy Endpoint

  18 weeks

Study Arms (2)

Tadekinig alfa

EXPERIMENTAL

Patients that showed response to treatment in the SAOL phase will receive Tadekinig alfa for up to 16 weeks.

Drug: Tadekinig alfa

0.9% sodium chloride

PLACEBO COMPARATOR

Patients that showed response to treatment in the SAOL phase will receive placebo comparator for up to 16 weeks.

Other: 0.9% sodium chloride

Interventions

Tadekinig alfa DRUG

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.

Also known as: IL-18BP, r-hIL-18BP

Tadekinig alfa

0.9% sodium chloride OTHER

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.

0.9% sodium chloride

Eligibility Criteria

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

You may qualify if:

• 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.)
• 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.
• Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥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.
• 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.

You may not qualify if:

• Patients with life-threatening co-morbidities not associated with the underlying NLRC4-mutation or XIAP deficiency
• Positive test for or prior history of HIV, Hepatitis B or Hepatitis C (serology)
• Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy
• Presence of life threatening infections
• Oncologic causes of symptoms; current or previous history of malignancy
• Presence of CNS manifestations (i.e. seizures, altered mental status, signs of increased intracranial pressure, chronic papilledema, loss of vision, other sensorineural deficiencies, etc.)
• 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
• 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
• Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent
• Hypersensitivity to the active substance or one of the excipients of the investigational product

Sponsors & Collaborators

• AB2 Bio Ltd.: lead

Study Sites (9)

UCSD _ Department of Pediatrics / Rady Children's Hospital

La Jolla, California, 92056, United States

Location

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, 30322, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Texas Children's Hospital _ Baylor College of Medicine

Houston, Texas, 77030, United States

Location

The Hospital for Sick Children

Toronto, Ontario, ON M5G 1X8, Canada

Location

CHU Sainte-Justine

Montreal, Providence, QC H3T 1C5, Canada

Location

Universitätsklinikum Freiburg, Centrum für Chronische Immundefizienz (CCI) - Paediatric Unit

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Related Publications (1)

• 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.

  PMID: 33128796 DERIVED

Related Links

• Sponsor details

MeSH Terms

Conditions

Lymphoproliferative Syndrome, X-Linked, 2

Interventions

interleukin-18 binding protein; Sodium Chloride

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Eduardo Schiffrin
• Organization: AB2 Bio Ltd.

eduardo.schiffrin@ab2bio.com

+41 21 694 00 40

Study Officials

• Ed M Behrens, MD

  Children Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Initial phase of 18 weeks is a single arm, open-label (SAOL) period where Tadekinig alfa is administered in addition to the standard of care treatment used for the control of flares. The SAOL period will be followed by an up to 16-week randomized withdrawal phase (RW). All patients who showed response to treatment at the end of the SAOL phase will be enrolled in the RW phase. In the RW phase patients will be randomized to either Tadekinig alfa or placebo.

Study Record Dates

• First Submitted: February 28, 2017
• First Posted: April 14, 2017
• Study Start: July 21, 2017
• Primary Completion: October 31, 2023
• Study Completion: November 2, 2023
• Last Updated: July 2, 2025
• Results First Posted: July 2, 2025

Record last verified: 2025-06

Locations

DE (1); US (6); CA (2)