Abstract Background: Iptacopan, the first-in-class oral complement factor B inhibitor that selectively inhibits the alternative pathway of the complement system, has been approved for the treatment (tx) of patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH). In 2023, prior to launch, a managed access program (MAP) was initiated to provide iptacopan (200 mg, twice daily) to PNH pts with high unmet clinical need who had exhausted the available tx options in clinical practice. Here, we report updated efficacy and safety outcomes from the MAP. Methods Adult pts with a confirmed diagnosis of PNH were eligible to be included in the MAP if they had received the required vaccinations. In addition, pts were required to fulfill the following eligibility criteria for participation: (i) an unsolicited request was submitted by a licensed physician; (ii) there was a lack of viable alternative therapy for serious/life-threatening conditions; (iii) they were ineligible for clinical trials or unable to participate; (iv) the risk of tx was justified by potential benefit; (v) they met additional medical criteria by experts or health authorities. At baseline (BL), most physicians requested 1 to 3 months of iptacopan tx. Retreatment requests (RRs) were permitted for pts benefiting from iptacopan tx. Categorical parameters collected at BL and RRs included: hemoglobin (Hb) range, reticulocyte count (RLC), lactate dehydrogenase (LDH) level, blood transfusion visits in the past 3 months, fatigue, tx satisfaction, and prior tx. Data were presented according to the prior tx status (complement inhibitor Ci –naïve and –experienced). Adverse events (AEs) were monitored continuously from the time of tx start by physicians. Results As of April 1, 2025, 212 pts across 27 countries received iptacopan tx as part of the MAP, with 50 discontinuing the program. The main reason for discontinuation was the transition to commercial supply of iptacopan in clinical practice (n=36) and 3 pts discontinued due to AEs. This analysis reports baseline characteristics and the outcomes at 2 successive retreatment visits (RR1 and RR2). Complete datasets were available for 95 pts at BL and RR1 (10 Ci-naïve, 85 Ci-experienced). Of these, 60 pts had complete datasets at BL and RR2 (6 Ci-naïve, 54 Ci-experienced). The proportion of pts previously treated with eculizumab, ravulizumab, pegcetacoplan, and danicopan was 71.6%, 37.9%, 13.7%, and 6.3%, respectively. The median age was 46.0 years (Interquartile range IQR, 35-59 years), 57.9% were females, and 57.9% were Caucasians. The median exposure to iptacopan was 202 days (IQR, 119-307 days). The proportion of pts with Hb ≤9.9/≥10-11.9/≥12 g/dL changed from 69.5%/14.7%/15.8% at BL to 22.1%/32.6%/45.3% at RR1 and 6.7%/25%/68.3% at RR2. At RR1 and RR2, 68 (71.6%) and 55 (91.7%) pts, respectively, had LDH levels below 1.5 × upper limit of normal vs 53 (55.8%) at BL. The number of pts who achieved RLC within normal range was 62 (65.3%) and 41 (68.3%) at RR1 and RR2, respectively, vs 28 (29.5%) pts at BL. The number of pts with ≥1 transfusion visits within the past 3 months decreased to 24 (25.3%) and 5 (8.3%) pts at RR1 and RR2, respectively, compared with 45 pts (47.4%) at BL. Furthermore, only 5 (5.3%) and 1 (1.7%) pts reported experiencing severe fatigue at RR1 and RR2, respectively, vs 29 (30.5%) pts at BL. Overall, 54 (56.8%) and 25 (26.3%) pts at RR1 and 47 (78.3%) and 7 (11.7%) pts at RR2 expressed being very satisfied and satisfied with their current therapy, respectively, vs only 8 (8.4%) and 9 (9.5%) pts at BL. Results for reported parameters in the Ci-experienced and Ci-naive population were consistent. Among 212 pts, 147 AEs were reported in 39 cases until April 1, 2025. Of these, 43 serious AEs were reported in 13 cases, including 4 break-through hemolysis/hemolysis and 4 infections, with only 1 infection suspected to be related to iptacopan. Conclusions The updated data from this MAP confirm hematological and clinical improvements with iptacopan in Ci-naive and Ci-experienced pts with PNH, with approximately 6 months of iptacopan therapy. Oral iptacopan monotherapy led to normalization of Hb and LDH level, and RLC, along with a higher proportion of pts achieving transfusion avoidance at retreatment visits compared to BL. Pts also reported notable improvements in fatigue and tx satisfaction. The safety profile of iptacopan in the PNH MAP population was consistent with the findings from clinical trials.
Rizk et al. (Mon,) studied this question.
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