Randomized, Double‑Blind, Placebo‑Controlled Dose‑Ranging and Efficacy Study of Oral SIR9900 in Adults with VEXAS Syndrome
- Trial ID
- 2025-524918-28-00
- Protocol
- SIR9900-GLB-202
- Sponsor
- Sironax USA Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to assess the safety, tolerability, and activity of two dose levels of SIR9900 (20 mg and 30 mg) versus placebo in Part A to identify the optimal dose for subsequent evaluation, and to evaluate the efficacy and safety of the selected dose versus placebo on overall clinical response in Part B, providing critical data for dose selection and therapeutic potential in VEXAS syndrome.
Secondary objectives include:
- Characterize the pharmacokinetic profile and population PK of SIR9900.
- Characterize the pharmacodynamic effect on inflammatory biomarkers and define exposure‑response relationships.
- Evaluate efficacy on overall clinical response and on the best overall response category (clinical biochemical response, partial response, stable disease, or non‑response).
- Quantify the number of flare‑free days.
- Assess hematologic improvements (hemoglobin and platelet counts).
- Measure change in health‑related quality of life, including fatigue, physical function, and sleep disturbance, as well as other QOL domains.
- Monitor safety and tolerability throughout the study.
Participants
The trial enrolled 86 participants, comprising both male and female adults aged ≥ 18 years, who met the clinical definition of VEXAS syndrome confirmed by a pathogenic UBA1 mutation. All subjects had documented involvement of at least one organ system (cutaneous, vascular, musculoskeletal, ocular, periorbital, genitourinary, or pulmonary) within the six months preceding enrollment and were receiving a stable glucocorticoid regimen of 15–45 mg/day prednisone or prednisolone for at least ten days. Inclusion required a Karnofsky Performance Status of ≥ 50 % and adequate organ function, including liver enzymes ≤3 × ULN, total bilirubin ≤2 × ULN, creatinine clearance ≥30 mL/min, absolute neutrophil count ≥500/µL, platelet count ≥25 × 10⁹/L, and peripheral blasts <5 %. Participants of child‑bearing potential adhered to contraceptive requirements, and females who were pregnant, lactating, or not meeting contraceptive criteria were excluded. The population was defined as vulnerable, reflecting the serious nature of the underlying disease, and no additional lifestyle restrictions beyond ongoing glucocorticoid therapy were stipulated.
Plans and Procedures
The study is a VEXAS Syndrome investigation employing a randomized, double‑blind, placebo‑controlled design with two sequential parts. Part A is a dose‑ranging phase comparing oral SIR9900 20 mg, SIR9900 30 mg, and matching placebo to assess safety, tolerability, and early activity; Part B uses the optimal dose from Part A to evaluate efficacy and safety versus placebo over a 52‑week period. Participants undergo a screening visit to confirm eligibility, including genetic confirmation of a UBA1 mutation and assessment of organ involvement, followed by a baseline visit on Day 1 when the first dose is administered. Subsequent study visits occur at weeks 1, 4, 12, 24, 48, and 52 for clinical evaluation, laboratory testing, pharmacokinetic sampling, and adverse‑event monitoring. The end‑of‑study visit at week 52 includes final efficacy assessments and safety follow‑up. Participant involvement therefore spans approximately one year from the first dose to the final visit. Early termination may occur for any of the following: occurrence of a serious adverse event, inability to taper glucocorticoids to ≤10 mg/day, protocol‑defined disease flare, or withdrawal of consent. The overall trial recruitment period is planned from 15 April 2026 to 15 April 2028.
Treatment
The investigational product, SIR9900, is supplied as an oral tablet. In the dose‑ranging phase, participants receive either a 20 mg or a 30 mg daily dose, administered once daily by mouth. The tablet formulation is identical for both dose levels, and dosing is continued throughout the treatment period as defined in the protocol.
The control arm utilizes a matching placebo tablet, which contains no active pharmaceutical ingredient. The placebo is identical in appearance, size, and packaging to the active tablet and is administered orally once daily on the same schedule as the active treatment.
All study medication is dispensed in labeled containers with a predetermined quantity sufficient for each treatment cycle. Participant compliance is monitored through pill counts at each study visit, electronic dosing diaries, and, when applicable, plasma concentration assessments. Dosing adjustments or interruptions are recorded according to predefined safety criteria, and adherence data are incorporated into the efficacy and safety analyses.
Efficacy
The primary efficacy assessment is the proportion of participants achieving overall clinical response (OCR) by the end of week 24. OCR is determined by a predefined clinical algorithm that incorporates disease activity, glucocorticoid tapering success, and absence of protocol‑defined flares. This endpoint is evaluated at the week 24 visit for each participant.
Secondary efficacy parameters include:
- Mean plasma concentration of SIR9900 measured at weeks 1, 12, 24, 48, and 52.
- Inflammatory biomarkers—C‑reactive protein (CRP), erythrocyte sedimentation rate (ESR), and ferritin—assessed at baseline and at regular intervals through week 52.
- Cumulative glucocorticoid dose recorded throughout the treatment period.
- Number of flare‑free days while receiving glucocorticoid ≤10 mg/day.
- Erythroid response (increase in hemoglobin) in participants with baseline hemoglobin < 10 g/dL and platelet response (increase in platelet count) assessed at any time point.
Biomarker levels and plasma drug concentrations are quantified using validated laboratory assays on collected blood samples. Glucocorticoid dosing, flare occurrences, and hematologic responses are captured through standardized case report forms and routine clinical laboratory evaluations. All efficacy data are analyzed according to the pre‑specified statistical analysis plan, with primary and secondary endpoints evaluated at the designated timepoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants should understand and be willing to comply with the study procedures, voluntarily participate in the study, and be able to provide written informed consent. 2. Participants will be male or female at least 18 years of age at the time of signing the informed consent form (ICF). 3. Participants must have documented evidence of a pathogenic mutation at methionine-41 (M41) or neighboring splice site mutation (c.118-1, c.118-2) position in UBA1 mutation based on myeloid next-generation sequencing (NGS), droplet digital polymerase chain reaction (ddPCR), or Sanger sequencing in peripheral blood or bone marrow samples. 4. Participants must have current or documented evidence of past involvement within 6 months prior to enrollment of at least 1 of the following organ systems by VEXAS syndrome: cutaneous (e.g., neutrophilic dermatosis, cutaneous vasculitis), vasculature (e.g., vasculitis), musculoskeletal (e.g., chondritis, arthritis), ocular (e.g., uveitis, scleritis), periorbital (e.g., periorbital edema), genitourinary (e.g., epididymitis), or pulmonary (e.g., alveolitis). 5. Participants will be receiving ongoing GC therapy for treatment of VEXAS syndrome (stable prednisone or prednisolone dose of 15-45 mg/day for at least 10 days prior to enrollment). Note that patients who are stable on GC doses of 10-14 mg/day in addition to another non-GC anti-inflammatory therapy at Screening who have a previously documented VEXAS flare on a GC dose ≥10 mg/day may be eligible provided that their GC dose is escalated to 15-45 mg/day after washout of non-GC anti-inflammatory therapy. 6. Participants will have a Karnofsky Performance Status ≥50%. 7. Participants will have adequate organ function, meeting all the following criteria within 30 days prior to enrollment: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN Total bilirubin (TBIL) ≤2 × ULN (≤4× ULN in the setting of Gilbert's syndrome) Creatinine clearance (CrCl) ≥30 mL/min based on the Cockcroft-Gault formula Absolute neutrophil count ≥500/μL Prothrombin time (PT) or international normalized ratio (INR) ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation) Partial thromboplastic time (PTT) or activated PTT ≤1.5 × ULN (unless prolonged due to therapeutic anticoagulation) Platelet count ≥ 25 × 109/L Peripheral blasts < 5% 8. Sex and contraceptive barrier requirements: • Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Females must not be lactating or pregnant at screening or baseline as documented by a negative beta-human chorionic gonadotropin (β-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 7 days before the first dose of study intervention. All females will be considered of childbearing potential unless they are postmenopausal (at least 12 months consecutively amenorrheic, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy) at least 1 month before dosing. Due to the limit of words allowed by the CTIS please refer to the protocol for the details on the contraception requirements.
Exclusion Criteria
- Prior allogenic hematopoietic stem cell transplant (allo-HSCT) or solid organ transplant (other than corneal). 2. Current use of systemic GCs for conditions other than VEXAS syndrome, which, in the opinion of the Investigator, would interfere with adherence to a GC taper regimen and/or assessment of efficacy. 3. More than one prior admission to an intensive care unit due to a VEXAS Syndrome flare within the prior 6 months. 4. Received ≥9 units of intensive red blood cell (RBC) transfusions in the 90 days prior to enrollment. 5. Known concurrent MDS requiring antineoplastic treatment, or allo-HSCT, or known high-risk or very high-risk MDS based on the Revised International Prognostic Scoring System (IPSS-R); Patients with MDS who do not meet these criteria may enroll. 6. Malignancy within 1 year prior to enrollment with the exception of MDS (per exclusion criterion), curatively treated non-melanoma skin cancer, or curatively treated carcinoma in situ. Patients with pre-malignant hematologic conditions (e.g., monoclonal gammopathy of unknown significance [MGUS], clonal cytopenia of unknown significance) may enroll. 7. Exposure to HMAs within 6 months prior to enrollment, or exposure to more than 4 cycles of HMAs at any time. 8. Exposure to non-GC anti-inflammatory therapy or hematologic support therapy within protocol defined timeframes prior to enrollment. (1See washout periods below.) 9. Exposure to anti-platelet therapy with the exception of low-dose aspirin (≤100 mg daily) within 28 days prior to enrollment. 10. Known concomitant multiple myeloma, or serum M-protein ≥3 g/dL, involved to uninvolved free light chain (FLC) ratio ≥100, or involved FLC level ≥100 mg/dL. Patients with MGUS may enroll. 11. Exposure to prescription medicines or other products that are potential index substrates of CYP1A2 with narrow therapeutic window, strong inhibitors/inducers of CYP3A, or strong inhibitors of CYP2C8 within 5 half-lives prior to dosing (refer to Protocol Appendix 1). These medications are also prohibited throughout the study (see Protocol Section 9.2.2). 12. Significant recent bleeding history defined as National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 within 3 months prior to enrollment, unless precipitated by an inciting event. 13.In the opinion of the investigator, history of clinically significant cardiovascular disease, or clinically significant abnormalities in rhythm or conduction during Screening ECG, including: a. Severe cardiac event (CTCAE grade ≥3) within 3 months prior to enrollment b. Heart failure resulting in limitations during ordinary activity. 14. Arterial or venous thrombotic or embolic events, including deep vein thrombosis, pulmonary embolism, and cerebrovascular accident (including transient ischemic attacks), within 60 days prior to enrollment. 15. Moderate or severe hepatic impairment that meets criteria for Child-Pugh Class B or C, or active viral hepatitis. 16. Uncontrolled human immunodeficiency virus (HIV) off antiretrovirals, or on antiretrovirals with detectable viral load. 17. Positive QuantiFERON (or other interferon gamma release assay) during Screening. 18. Concurrent enrollment in another interventional study, or treatment with an experimental therapy within 28 days or five half-lives prior to enrollment, whichever is longer. 19. Acute, active infection requiring systemic antimicrobial treatment at the time of enrollment. Exceptions are made for prophylactic antibiotics or chronic antibiotic therapy for non-acute conditions. 20. Known hypersensitivity to SIR9900 or any of its inactive ingredients.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Yet Recruiting | 15 Apr 2026 | 24 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SIR9900 10mg | Test | TABLET | ORAL | 30 | 48 | PRD13285116 |
Sir9900 Placebo | Placebo | N/A | — | — | — | N/A |