therapeutic use of tadekinig alfa in nlrc4 mutation and xiap deficiency

Conditions: NLRC4-MAS; XIAP Deficiency

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.

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)

Eligibility criteria:
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