Safety and Efficacy of Iptacopan in Patients With High-Risk Transplantation-Associated Thrombotic Microangiopathy

Inclusion criteria

• Age ≥12 years at the time of ICF signature.
• Previous recipient of autologous or allogeneic HSCT.
• Persistent TA-TMA despite initial management of potential triggers (e.g., CNI/mTOR inhibitor reduction, infection or GVHD treatment), with TMA activity sustained for ≥72 hours post-intervention.
• TA-TMA diagnosis, confirmed ≤14 days prior to or during screening by either biopsy-proven microthrombi or ≥4 of the following:

(1) LDH > ULN (2) Proteinuria (rUPCR ≥1 mg/mg) (3) Hypertension (age-adjusted) (4) New-onset thrombocytopenia (platelet decrease ≥50%, count ≤50,000/mm³, or transfusion-refractory) (5) New-onset anemia or increased transfusion need (6) Microangiopathy on blood smear (schistocytes ≥1%) or biopsy (7) Elevated terminal complement complex (C5b-9) 5. High-risk TMA features (per 2023 consensus), meeting ≥1 criterion:

• LDH ≥2× ULN
• Elevated sC5b-9
• Proteinuria (rUPCR ≥1 mg/mg)
• Multi-organ dysfunction syndrome (MODS)
• Concurrent Grade II-IV acute GVHD
• Active systemic infection 6. Able to receive oral medication. 7. Failure of first-line therapy (e.g., CNI/mTOR inhibitor adjustment, plasma exchange, rituximab, defibrotide), excluding prior complement inhibitors.

• Life expectancy >8 weeks. 9. Required vaccination against encapsulated bacteria (meningococcal, pneumococcal) per local guidelines, administered ≥2 weeks prior to first dose. If vaccination is delayed, antimicrobial prophylaxis is required.

• For subjects unable to receive meningococcal vaccines, antibiotic prophylaxis must be continued throughout treatment and for 8 months post-last dose.

• For subjects of reproductive potential: agreement to use effective contraception and, for females, a negative pregnancy test at screening.

• Provision of signed informed consent and compliance with study procedures.

Exclusion criteria

• Known familial or acquired ADAMTS13 deficiency (activity <5%).
• Known Shiga toxin-associated HUS (positive Shiga toxin assay or culture).
• Positive direct Coombs test with clinically significant immune-mediated hemolysis per investigator.
• Clinically overt disseminated intravascular coagulation (DIC) according to ISTH criteria.
• Bone marrow/graft failure.
• Known HIV infection (confirmed by testing within 6 months prior to screening).
• Active meningococcal disease.
• Septic shock requiring vasopressor support within 7 days prior to enrollment.
• Pregnant or breastfeeding.
• Any concurrent or prior medical condition unrelated to TA-TMA that, in the opinion of the investigator or sponsor, could increase risk or confound study outcomes (e.g., significant cardiac, pulmonary, renal, endocrine, or hepatic disease).
• All-cause respiratory failure requiring mechanical ventilation within 72 hours prior to enrollment.
• Acute/chronic heart failure with left ventricular ejection fraction ≤40%.
• Prior treatment with iptacopan, eculizumab, or other complement inhibitors within 60 days before first study dose.
• Use of any investigational agent within 30 days or 5 half-lives (whichever is longer) prior to screening.
• Recurrent primary malignancy or post-transplant lymphoproliferative disorder (PTLD).