Iptacopan Treatment Improves Clinical Parameters in a Real-World Cohort with Paroxysmal Nocturnal Hemoglobinuria: Evidence from a Managed Access Program

Background: Paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematopoietic stem cell disorder, is life-threatening and associated with complement-mediated hemolysis, thrombosis, and bone marrow failure. While several treatment options for PNH are available, remaining unmet clinical need and access to effective therapies continue to be a challenge for some patients. Iptacopan is the first oral, proximal complement inhibitor that targets Factor B to inhibit the alternative pathway. In 2023, prior to launch, a managed access program (MAP) was initiated to provide iptacopan (200 mg, twice daily) to PNH patients with high unmet clinical need who have exhausted available treatment options. Here, we focus on outcomes of MAP patients with PNH from 23 countries, for whom their physicians had initiated iptacopan treatment.

Methods: In the ongoing MAP,patients were eligible for participation if: (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 treatment was justified by potential benefit, (v) they met additional medical criteria by experts or health authorities. Adults (≥18 years) with confirmed PNH diagnosis and who had received the required vaccinations were included. At baseline (BL), physicians included their patients in the MAP by requesting treatment initiation with iptacopan for a duration ranging from 1 to 3 months. Subsequently, requests for retreatment could be made at any time for patients benefiting from treatment, to ensure uninterrupted treatment. Categorical parameters were collected at the time of MAP enrollment (BL) and at request for retreatment (RR) to evaluate hemoglobin range (Hb [g/dL]), lactose dehydrogenase (LDH) above normal range (yes/no), reticulocyte count within normal range (yes/no), number of blood transfusion visits in the past 3 months, fatigue status, overall treatment satisfaction, and treatments received prior to iptacopan therapy.

Results: As of June 20, 2024,74 patients were treated with iptacopan, and 5 patients discontinued the MAP for reasons not related to adverse events, such as inactivity or no response from treating physician; 35 patients had complete datasets available at both baseline and RR and were included in the analysis. Patients had a median age of 51.0 years (IQR 41.0-65.0), 21 (60.0%) were female, and 25 (65.7%) were Caucasian and their median exposure to iptacopan was 32 (IQR 22-53; min 5, max 89) days. Within this exposure time, 28 (80%) patients at the time of RR had achieved Hb level ≥10 g/dL vs 16 (45.7%) patients at BL, of which 14 (40.0%) patients at the time of RR achieved Hb level ≥12 g/dL vs 10 (28.6%) patients at BL. In total, 25 (71.4%) patients had LDH levels below 1.5 × upper limit of normal vs 20 (57.1%) patients at BL, and 22 (62.9%) patients achieved reticulocyte count within normal range vs 16 (45.7%) patients at BL. In total, 3 (8.6%) patients at the time of RR had ≥2 blood transfusion visits in the past 3 months vs 11 (31.4%) patients at BL. No patients reported severe fatigue at the time of RR vs 13 (37.1%) patients at BL. Overall, 12 (34.3%) and 17 (48.6%) patients reported being satisfied and very satisfied with their current therapy at the time of RR vs 4 (11.4%) and 6 (17.1%) patients who were satisfied or very satisfied with their therapies at BL, respectively. Overall, 5 (14.3%) patients were complement treatment-naïve, and 30 (85.7%) patients were reported to receive ≥1 prior complement inhibitor therapies including eculizumab (23 [65.7%]), ravulizumab (15 [42.9%]), pegcetacoplan (7 [20.0%]), vemircopan (6 [17.1%]), and others. The safety profile of MAP population was consistent with that reported in randomized clinical trials.

Conclusion: This MAP data analysis demonstrates that with 1 month of iptacopan therapy, hematological and patient-oriented parameters were improved in both complement inhibitor-naïve and -experienced patients in this real-world setting. At the time of iptacopan retreatment request, a higher proportion of patients reported near normal Hb levels and reticulocyte count, had a reduced number of transfusion visits, and improved fatigue and treatment satisfaction. Additional long-term results may provide better understanding of iptacopan safety and efficacy in real-world patients with PNH.

Snellman:Novartis: Current Employment, Current equity holder in publicly-traded company. Tiwari:Novartis Healthcare Pvt. Ltd.: Current Employment. Khan:Novartis Healthcare Pvt. Ltd.: Current Employment, Current equity holder in publicly-traded company. Rizk:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Pilipovic:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company.