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

A Prospective, Multicenter, Single-Arm Study: Safety and Efficacy of Iptacopan in the Treatment of High-Risk Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy (TA-TMA)

The goal of this clinical trial is to evaluate the efficacy and safety of Iptacopan as a second-line treatment for high-risk hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA). Iptacopan is a selective oral small-molecule complement factor B inhibitor. It acts by inhibiting factor B, blocking the formation of C3 convertase, reducing C3b deposition, thereby suppressing C5 convertase (C3bBbC3b) and ultimately decreasing the formation of the membrane attack complex (MAC), which is expected to mitigate endothelial damage in TA-TMA pathology. The main questions this study aims to answer are:

• Does Iptacopan improve 6-month overall survival in high-risk TA-TMA patients?
• What adverse events do participants experience while taking Iptacopan?
• Does Iptacopan provide hematological response and organ function recovery in TA-TMA patients? In this prospective, multicenter, open-label, single-arm Phase II study, all participants will receive Iptacopan treatment. The primary endpoint of this study is the 6-month overall survival rate from TA-TMA diagnosis. Secondary endpoints include safety evaluation, hematological response, and organ function recovery.

During the study, participants will:

• Receive Iptacopan treatment according to protocol
• Undergo regular assessments for safety and efficacy monitoring
• Be followed for up to 24 months post-treatment initiation

Inclusion Criteria:

1. Age ≥12 years at the time of ICF signature.
2. Previous recipient of autologous or allogeneic HSCT.
3. 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.
4. 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:

1. LDH ≥2× ULN
2. Elevated sC5b-9
3. Proteinuria (rUPCR ≥1 mg/mg)
4. Multi-organ dysfunction syndrome (MODS)
5. Concurrent Grade II-IV acute GVHD
6. 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.

8. 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.

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

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

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

Exclusion Criteria:

1. Known familial or acquired ADAMTS13 deficiency (activity <5%).
2. Known Shiga toxin-associated HUS (positive Shiga toxin assay or culture).
3. Positive direct Coombs test with clinically significant immune-mediated hemolysis per investigator.
4. Clinically overt disseminated intravascular coagulation (DIC) according to ISTH criteria.
5. Bone marrow/graft failure.
6. Known HIV infection (confirmed by testing within 6 months prior to screening).
7. Active meningococcal disease.
8. Septic shock requiring vasopressor support within 7 days prior to enrollment.
9. Pregnant or breastfeeding.
10. 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).
11. All-cause respiratory failure requiring mechanical ventilation within 72 hours prior to enrollment.
12. Acute/chronic heart failure with left ventricular ejection fraction ≤40%.
13. Prior treatment with iptacopan, eculizumab, or other complement inhibitors within 60 days before first study dose.
14. Use of any investigational agent within 30 days or 5 half-lives (whichever is longer) prior to screening.
15. Recurrent primary malignancy or post-transplant lymphoproliferative disorder (PTLD).