Iptacopan Monotherapy in Patients with Cold Agglutinin Disease: Phase II Study Results
Authors: Röth Alexander , Barcellini Wilma , Ademokun Christine , Chitnis Shripad , Matviykiv Sofiya , Vitaliti Alessandra , Chen Chi , Katsanou Vasiliki , Chawla Raghav , Al-Samkari Hanny 
Published: December 2024

Background: Cold agglutinin disease (CAD) is a rare, autoimmune, hemolytic anemia triggered by cold-reacting autoantibodies targeting the I antigen on the red blood cell surface. Standard of care for acute CAD has consisted of blood transfusions, plasmapheresis, high-dose steroids and/or early use of rituximab. More recently, several complement inhibitors have shown clinical benefit in refractory CAD, with the classical pathway inhibitor sutimlimab (Röth et al. N Engl J Med 2021) obtaining US approval for this indication in 2022. To date, no effective oral treatments are available for CAD. Iptacopan is a first-in-class, oral, selective inhibitor of factor B, which is a key component of the complement alternative pathway and amplification loop. Iptacopan has shown positive efficacy across several complement-driven diseases and was recently approved for use in patients (pts) with paroxysmal nocturnal hemoglobinuria.
Aim: To evaluate the efficacy and safety of iptacopan in pts with primary CAD.
Methods: CLNP023L12201 (NCT05086744) is a multicenter, open-label, non-randomized, Phase II basket study of iptacopan monotherapy in adult pts with autoimmune cytopenias. In the CAD cohort, eligible pts had primary CAD and evidence of sustained anemia (hemoglobin [Hb] &lt;10 g/dL) and ongoing hemolysis after ≥1 unique prior CAD therapy. In Part A, pts received iptacopan 200 mg twice daily for 12 weeks. At the end of Part A, and after a ≤4-week washout period, pts who met the primary endpoint of clinically meaningful Hb response or who had investigator-assessed clinical benefit were allowed to enter a treatment extension for ≤24 months (Part B). The primary endpoint of a clinically meaningful response was defined as an Hb increase of ≥1.5 g/dL above baseline that was sustained for ≥2 consecutive weeks without the use of rescue therapy during Part A. Secondary endpoints included time to first response, duration and magnitude of response, relevant disease biomarker levels and safety/tolerability. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores were an exploratory endpoint.
Results: The study has completed enrolment, with 10 CAD pts. All pts were white females with a mean age of 66.7 years, a mean of 2.7 (range: 1-6) unique prior therapies and mean baseline Hb and lactate dehydrogenase (LDH) of 8.7 g/dL (range: 6.8-9.9) and 447 U/L (279-598), respectively. Nine pts (90%) completed the full Part A treatment period. Five pts (50%) met the primary endpoint in Part A of a clinically meaningful Hb response without rescue therapy. At Week 12, mean Hb was 10.5 g/dL (range: 8.5-11.3), with a mean increase from baseline of 1.8 g/dL (range: −0.2 to 3.8). The mean time to first response was 40.0 days (range: 23-63), and the mean duration of response during the 12-week Part A treatment period was 46.2 days (range: 28-63). At Week 12, mean LDH was 216 U/L (range: 143-344), with a mean decrease from baseline of 255 U/L (range: −409 to −121). Positive trends in other disease biomarkers, including bilirubin, reticulocytes and haptoglobin, and FACIT-fatigue scores were also observed. Eight pts continued to Part B (all 5 who met the primary endpoint plus 3 who experienced an investigator-assessed clinical benefit). Improvements in Hb and disease biomarkers were sustained in Part B in most pts. Overall, iptacopan was well tolerated. Eight pts (80%) experienced ≥1 treatment-emergent adverse event (TEAE), most of which were mild in severity. Two pts discontinued treatment because of TEAEs (1 had increased alanine aminotransferase and aspartate aminotransferase [suspected to be treatment related]; 1 had recurrent breast cancer [not suspected to be treatment related]). Two pts had serious adverse events (1 had increased blood creatinine and acute kidney injury; 1 had spinal fracture), but none were suspected to be treatment related.
Conclusions: In this Phase II study, iptacopan monotherapy showed encouraging efficacy in pts with CAD, with half of the pts meeting the primary endpoint of a clinically meaningful Hb response. Increases in Hb levels were sustained and accompanied by normalization of LDH levels, suggesting good control of intravascular hemolysis. Positive trends in other hemolytic parameters and FACIT-fatigue scores were also observed. Iptacopan was well tolerated, with no unexpected safety findings. These results are promising but require confirmation in a larger study.