study to evaluate the efficacy, safety and tolerability of mas825 in patients with monogenic il-18 driven autoinflammatory diseases, including nlrc4-gof, xiap deficiency, or cdc42 mutations

Conditions: NLRC4-GOF, AIFEC (Autoinflammation With Infantile Enterocolitis), XIAP Deficiency, CDC42 Mutations

Summary: this study is a phase 2 trial designed to evaluate the clinical efficacy, safety, and tolerability of mas825 in patients with nlrc4-gof, xiap deficiency, or cdc42 mutations.

this is a three-period study, with an open-label, single-arm active treatment in period 1 followed by a randomized-withdrawal, double-blinded, placebo-controlled design in period 2, and an open label, long-term safety follow-up in period 3. the total study duration is approximately 3 - 4 years. patients who enter period 2 will be randomized to mas825 or matching placebo in a 1:1 ratio. cohort 1 patients will complete all periods of the study, which will take approximately 4 years. cohort 2: patients who are receiving mas825 in a novartis managed access program with a diagnosis of nlrc4-gof, xiap deficiency, or cdc42 mutation who meet criteria will be eligible to directly enter into period 3 for open-label long-term safety follow-up. cohort 2 patients will be in the study for approximately 3 years.

Eligibility criteria:
inclusion criteria: for all patients: 1. male and female patients weighing at least 3 kg 2. written informed consent by parent(s)/legal guardian(s) for the pediatric patients and assent by the pediatric patient (depending on local requirements) must be obtained before any study-specific assessment is performed. for adult patients, written informed consent by patients capable of giving consent, or when the patient is not capable of giving consent, by his/her legal/authorized representative (if allowed according to local requirements). cohort 1 specific inclusion criteria: 3. patients with a genetic diagnosis of either nlrc4-gof, xiap deficiency, or cdc42 mutation 4. clinical history and investigations consistent with autoinflammation and infantile enterocolitis (aifec/nlrc4-gof), xiap or cdc42. xiap patients must have persistent disease or be resistant to escalating therapy. 5. at first treatment, evidence of active disease as assessed by inflammatory markers and pga cohort 2 specific inclusion criteria: 6. patients with a genetic diagnosis of nlrc4-gof, xiap deficiency, or cdc42 mutations who are being treated with mas825 in a novartis managed access program (map). exclusion criteria: 1. history of hypersensitivity to any of the study drugs or to drugs of similar chemical classes or to any of the excipients. 2. signs and symptoms, in the judgment of the investigator, of clinically significant active bacterial, fungal, parasitic or viral infections, excluding chronic epstein-barr virus (ebv). - covid-19 specific: if in line with health and governmental authority guidance, it is highly recommended that testing to exclude covid-19 using pcr or comparable approved methodology be completed within 1 week prior to first dosing. 3. any conditions or significant medical problems, which in the opinion of the investigator places the patient at unacceptable risk for mas825 therapy 4. previous treatment with anti-rejection and/or immunomodulatory drugs within the past 28 days or 5 half-lives (whichever is the longer) for immunomodulatory therapeutic antibodies (or as listed in the prohibited medications section) prior to mas825 treatment with the exceptions of glucocorticoids, cyclosporin and targeted binding or blocking therapies. 5. a positive hiv test result at screening. evidence of prior testing within 3 months is sufficient. 6. a positive hepatitis b surface antigen (hbsag) or hepatitis c test result at screening. evidence of prior testing within 3 months is sufficient. 7. presence of tuberculosis infection as defined by a positive tb test at screening. evidence of prior testing within 3 months is sufficient. 8. live vaccinations within 1 month prior to mas825 treatment, during the trial, and up to 3 months following the last dose. 9. pregnant or nursing (lactating) females. 10. female patients of child-bearing potential (or tanner stage 2 or above) who are or might become sexually active, agree to use highly effective contraceptive methods to prevent pregnancy while on mas825 therapy 11. patients weighing \>160 kg at screening. 12. for cdc42 mutation patients: takenouchi-kosaki syndrome - cdc42 mutations associated with a diverse syndrome characterized by variable development delays, cardiac, brain and hematological abnormalities.

Keywords: nlrc4-gof aifec enterocolitis autoinflammation mas nlrc4 (scan4) xiap deficiency cdc42 mutations