Highlights
- Iptacopan, a first-in-class oral factor B inhibitor, achieved the primary hemoglobin response endpoint in 50% of patients with Cold Agglutinin Disease (CAD).
- The mean increase in hemoglobin for CAD patients was 2.2 g/dL by week 12, accompanied by improvements in markers of hemolysis and fatigue.
- No patients with Immune Thrombocytopenia (ITP) met the primary platelet response endpoint (≥ 50 × 10⁹/L), suggesting a limited role for the alternative complement pathway in this specific ITP cohort.
- Iptacopan was well tolerated in both groups, with most adverse events being mild and no unexpected safety signals reported.
Introduction: The Complement System in Hematologic Pathologies
The complement system serves as a cornerstone of the innate immune response, yet its dysregulation is increasingly recognized as a primary driver of various hematologic disorders. Cold Agglutinin Disease (CAD) and Immune Thrombocytopenia (ITP) are two such conditions where immune-mediated destruction of blood components leads to significant morbidity. While the classical pathway is well-characterized in CAD, the role of the alternative pathway—specifically mediated by factor B—has become a target of intense clinical interest. Iptacopan, a selective, small-molecule inhibitor of complement factor B, represents a potential paradigm shift: an oral monotherapy targeting the alternative pathway to prevent extravascular hemolysis and, potentially, platelet destruction.
Background and Disease Burden
Cold Agglutinin Disease is a rare form of autoimmune hemolytic anemia characterized by IgM autoantibodies that bind to red blood cell (RBC) antigens at low temperatures. This binding triggers the classical complement pathway, leading to C3b opsonization and subsequent extravascular hemolysis in the liver. Patients suffer from chronic anemia, severe fatigue, and cold-induced circulatory symptoms. Current therapies, such as rituximab or the C1s inhibitor sutimlimab, often require intravenous administration and may not fully address the alternative pathway’s amplification loop.
Immune Thrombocytopenia, conversely, is characterized by platelet destruction and impaired production. While primarily considered an IgG-mediated process involving Fcγ receptors on macrophages, emerging evidence suggests that complement activation may exacerbate platelet clearance in a subset of patients. Given the high burden of disease and the need for durable, oral treatments in both conditions, the evaluation of iptacopan via a basket trial design offers a streamlined approach to assessing its therapeutic breadth.
Study Design: The Global Phase 2 Basket Trial
This global, multicenter, phase 2 basket study (NCT05086744) enrolled adult patients who had failed at least one prior therapy. The trial was designed to evaluate the efficacy, safety, and pharmacokinetics of iptacopan monotherapy. Nineteen patients were enrolled: 9 with primary ITP and 10 with primary CAD.
The primary endpoint for the ITP cohort was a platelet response defined as ≥ 50 × 10⁹/L, sustained for at least 2 consecutive weeks during the first 12 weeks of treatment without rescue therapy. For the CAD cohort, the primary endpoint was a hemoglobin response, defined as an increase of ≥ 1.5 g/dL from baseline, sustained for at least 2 consecutive weeks during the same period. Secondary endpoints included the time to response, duration of response, safety/tolerability, and patient-reported outcomes via the FACIT-Fatigue scale.
Key Findings in Cold Agglutinin Disease
The results for the CAD cohort were particularly encouraging. Five out of ten patients (50%) achieved the primary endpoint. Beyond the binary response, the quantitative improvements were clinically significant. The mean increase in hemoglobin levels from baseline to week 12 was 2.2 g/dL. This improvement in oxygen-carrying capacity translated into tangible benefits for patients, as evidenced by improved scores on the FACIT-Fatigue scale, which measures the impact of anemia on daily life.
Mechanistically, the efficacy of iptacopan was supported by a reduction in markers of hemolysis. Improvements were noted in lactate dehydrogenase (LDH) levels, total bilirubin, and reticulocyte counts. These findings suggest that by inhibiting factor B, iptacopan effectively blunts the alternative pathway amplification loop, thereby reducing C3-mediated extravascular hemolysis. The oral nature of the drug provides a potential advantage over existing parenteral complement inhibitors, offering greater convenience for long-term management.
Key Findings in Immune Thrombocytopenia
In contrast to the success seen in CAD, the ITP cohort did not meet the protocol-defined primary endpoint. None of the nine patients achieved a sustained platelet count of ≥ 50 × 10⁹/L. While some transient fluctuations in platelet counts were observed, they did not meet the rigorous criteria for clinical response. This outcome suggests that, for the broad population of patients with primary ITP who have failed prior therapies, the alternative complement pathway may not be the dominant mechanism driving platelet clearance.
It is important to note, however, that ITP is a highly heterogeneous disease. While this study did not find a benefit in the general ITP basket, it remains possible that a specific molecular endotype of ITP—perhaps those with high levels of complement deposition on platelets—might still benefit from such an approach. However, based on these phase 2 data, iptacopan monotherapy does not appear to be a viable strategy for unselected refractory ITP patients.
Safety and Tolerability
Safety is a paramount concern for complement inhibitors, given the role of the complement system in defending against encapsulated bacteria. In this study, iptacopan demonstrated a favorable safety profile. Most treatment-emergent adverse events (TEAEs) were categorized as mild (Grade 1 or 2). The most frequently reported TEAEs across both cohorts were headache (21%), asthenia (16%), fatigue (16%), and petechiae (16%). No unexpected safety signals or serious infections related to complement inhibition were reported during the study period. The tolerability of the drug was consistent across both the CAD and ITP groups, reinforcing the feasibility of factor B inhibition as a therapeutic strategy.
Expert Commentary: Mechanistic Insights
The divergent results of this trial provide important insights into the pathophysiology of these two hematologic disorders. In CAD, the alternative pathway serves as a critical amplification loop for C3b deposition, even when the initial trigger is the classical pathway (IgM-C1q). By blocking factor B, iptacopan interrupts this loop, significantly reducing the density of C3b on red cells and preventing their destruction by hepatic macrophages. This confirms that the alternative pathway is a ‘bottleneck’ in CAD hemolysis.
In ITP, the failure of iptacopan suggests that Fc-mediated phagocytosis and T-cell mediated destruction likely overwhelm any contribution from the complement system in most patients. Unlike red cells in CAD, which are primarily cleared via C3b opsonization, platelets in ITP are predominantly cleared via IgG-Fcγ receptor interactions in the spleen. Therefore, targeting the complement system alone may be insufficient to restore platelet counts in the absence of broader immune modulation.
Conclusion and Future Directions
The Phase 2 basket trial of iptacopan underscores the importance of targeted therapy in rare hematologic diseases. While the drug did not show efficacy in primary ITP, its performance in Cold Agglutinin Disease is highly promising. An oral, well-tolerated inhibitor of factor B could offer a significant advancement for CAD patients, providing a potent alternative to current injectable therapies. Future research should focus on the long-term durability of the response in CAD and investigate whether complement inhibition could be used as a synergistic adjunct in specific subsets of ITP patients who exhibit complement-mediated pathology.
Funding and ClinicalTrials.gov
This study was funded by Novartis Pharmaceuticals. ClinicalTrials.gov identifier: NCT05086744. The authors would like to thank the patients and their families for participating in this global clinical trial.
References
- Röth A, Barcellini W, Ademokun C, et al. Iptacopan for Immune Thrombocytopenia and Cold Agglutinin Disease: A Global Phase 2 Basket Clinical Trial. Am J Hematol. 2026;101(2):242-254.
- Roth A, et al. Sutimlimab in patients with cold agglutinin disease: results from the 26-week bi-weekly treatment period of the phase 3 CARDINAL study. Blood. 2021;136(24):2739-2749.
- Risitano AM, et al. Iptacopan in patients with paroxysmal nocturnal hemoglobinuria: a phase 2, multicentre, open-label, dose-finding study. The Lancet Haematology. 2021;8(5):e344-e354.
