EFFECTIVENESS AND SAFETY OF IPTACOPAN IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATIENTS WITH PERSISTENT ANEMIA AFTER C5 INHIBITION: THE REAL-WORLD EXPERIENCE OF THE FRENCH EARLY ACCESS PROGRAM

Iptacopan is the first oral monotherapy proximal complement inhibitor that controls both intravascular and extravascular hemolysis in Paroxysmal Nocturnal Hemoglobinuria (PNH) by targeting Factor B of the alternative complement pathway. Iptacopan was shown to be superior to anti-C5 in improving clinical parameters such as hemoglobin levels and red blood cell transfusions (RBCT) in patients with persistent anemia in a randomized controlled trial (APPLY-PNH trial). Iptacopan has been available in France since May 2, 2024, through an Early Access Program (EAP) for the treatment of adult patients with PNH who remain anemic despite C5 inhibition (C5i).  Here the authors report the results of the first analysis of the EAP.

Eligibility criteria to initiate iptacopan through compassionate use or EAP were: adult patients with PNH clone size ≥10%, hemoglobin (Hb) level <10 g/dL despite 6 months of C5i, required vaccinations, and validation by the French reference center multidisciplinary team.  In the ongoing EAP, clinical and biological data are captured at the time of treatment request, initiation and day 15 (D15), month 2 (M2), and every 2 months thereafter. The effective EAP launch occurred on June 19, 2024, and database lock (DBL) on November 8, 2024. Access was requested by 14 physicians for 30 patients; 29 were granted and one was refused due to unmet eligibility criteria. Four requests occurred before EAP launch and patients had initiated iptacopan via compassionate use. Twenty-five requests occurred after EAP launch; among them, 21 patients had initiated iptacopan and 4 patients had not yet started the treatment from which, one patient will never initiate treatment due to a deterioration of his general condition. Among the 25 granted requests after EAP launch, patients had a mean age of 49.3 ± 19.4 years, 16 (64.0%) were female. Seven (28%) had a history of thrombotic events and 13 (52.0%) required RBCT in the 12 months prior time of request, with an average number of 10.2 ± 11.5 transfusions per patient. 

Among the 21 who had initiated iptacopan after EAP launch, the mean treatment exposure was 0,9 ± 0,8 months. Mean Hb levels increased significantly and rapidly from 8.92 ± 1.45 g/dL at time of request to 11.89 ± 1.34 g/dL at D15, to 12,43 ± 1,23 g/dL at M2 (+4,13 ± 1,63 g/dL vs inclusion). One patient required transfusion at D15, and no patient required transfusion at M2. Overall, no patient discontinued iptacopan, there were no breakthrough hemolysis or thromboembolic events. One bacterial infection was reported; a cystitis (Klebsiella) which did not lead to any iptacopan modification or discontinuation. For the 4 patients who had initiated iptacopan via compassionate use the mean treatment exposure was 5,3 ± 2,8 months. Hb levels remained stable for all patients with the last measure at M4 of 12.63 ± 1.24 g/dL. No patient required RBCT.

This first analysis of French EAP shows that treatment with iptacopan in real-world permits a reduction of RBCT requirements with a significant increase in Hb levels within the first 15 days of treatment. There were no discontinuations and no new safety signals. The next analysis by the end of 2025 will provide additional long-term and quality of life results for a better understanding of iptacopan's safety and effectiveness in real-world patients with PNH. 

THE 2-YEAR SAFETY AND EFFICACY OF IPTACOPAN MONOTHERAPY IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) FROM APPLY- AND APPOINT-PNH STUDIES WHO ENTERED THE ROLL-OVER EXTENSION PROGRAM (REP)

Iptacopan, an oral factor B inhibitor approved as a monotherapy for treatment of adults with PNH, provided sustained improvement of hemoglobin (Hb) to near-normal levels, transfusion independence (TI), and decreased patient-reported fatigue in patients (pts) with persistent anemia despite anti-C5 treatment (APPLY-PNH) or who were complement inhibitor naïve (APPOINT-PNH).  Results from these phase 3 trials showed that the efficacy of iptacopan observed at Week 24 was sustained up to wk 48. The oral delivery method and the unique mechanism of action of iptacopan offer potential benefits over current treatments, warranting an assessment of its long-term therapeutic outcomes.

The purpose of the current analysis is to assess the long-term safety, tolerability, and efficacy of iptacopan monotherapy in pts with PNH who started treatment with iptacopan in APPLY- and APPOINT-PNH studies. Herein, we report the 2-year follow-up data. The REP is an ongoing, open-label, single-arm, multicenter, phase 3 study involving 59 centers globally. It enrolled pts, who completed phase 2 and 3 trials and benefited from iptacopan treatment, serving as the source for the current analysis.

Out of 136 pts treated with iptacopan in APPLY- and APPOINT-PNH, 128 (94.1%) were still on treatment at 2-year follow-up, 8 (5.9%) having discontinued treatment due to pregnancy (2), physicians' decision (2), adverse events (AEs) (1), delayed Institutional Review Board approval (1), and death (2). In this combined analysis set, 71.8% (89/124) pts achieved a sustained Hb of ≥12 g/dL, while 83.9% (104/124) had an Hb increase of ≥2 g/dL, both irrespective of RBC transfusions at 2 years. Mean (SD) Hb level (irrespective of RBC transfusion) at 2 years was 12.69 g/dL (2.022), with mean (SD) change from baseline (BL) of 3.9 g/dL (2.461). Mean (SD) LDH level was 300.37 (196.565) U/L. LDH <1.5 x ULN was observed in 88.7% (110/124) pts. TI was achieved in 90.4% pts. Mean (SD) Functional Assessment of Chronic Illness Therapy-Fatigue score was 43.0 (8.97) with mean change (SD) from BL of 10.0 (11.18). Overall, efficacy results were comparable among the APPLY-PNH REP, APPOINT-PNH REP, and the combined arms (Table).

The exposure-adjusted reporting rate of serious AEs (SAEs: 24.7 per 100 pt-years) during 2 years of treatment was similar to that observed in APPLY- and APPOINT-PNH over 24 wks (28.0 and 20.7 per 100 pt-years, respectively). The most common treatment-emergent AEs (reported in ≥10% of pts) were COVID-19 (46.3%), headache (21.3%), diarrhea (19.1%), upper respiratory tract infection (17.6%), nasopharyngitis (16.9%), abdominal pain (12.5%), nausea and vomiting (each 11.8%), pyrexia and breakthrough hemolysis [BTH] (each 11.0%).

The low exposure-adjusted rate of serious BTH over 2 years (1.1 events per 100 pt-years) was consistent with no serious BTH observed during 24 wks and 1 serious BTH during 48 wks. Major adverse vascular events were observed in 3 pts (4 events).

The 2-year data showed that iptacopan was well tolerated with no new safety signals and no increase in exposure-adjusted rates of AEs or SAEs with longer treatment duration. Sustained Hb ≥ 12 g/dL and LDH <1.5 x ULN in majority of pts at 2-year reflect comprehensive hemolysis control with iptacopan, accompanied by improvement in patient-reported fatigue. These findings continue to support oral iptacopan monotherapy as a potentially practice-changing treatment for pts with PNH.

APPULSE-PNH: ORAL IPTACOPAN MONOTHERAPY DEMONSTRATES CLINICALLY MEANINGFUL HEMOGLOBIN (HB) INCREASES IN PATIENTS (PTS) WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) AND HB ≥10 G/DL ON ANTI-C5 THERAPY

Many pts with PNH on anti-C5 remain anemic. Iptacopan, the first oral selective factor B inhibitor, had superior efficacy vs anti-C5 (eculizumab/ravulizumab) in pts with PNH and Hb <10 g/dL on anti-C5 in APPLY-PNH. The authors report primary efficacy and safety data from the single-arm, open-label, multicenter, Phase IIIb APPULSE-PNH trial (NCT05630001) in pts with PNH and Hb ≥10 g/dL in response to anti-C5 who switched to iptacopan. Fifty-two pts were enrolled: mean age was 46.0 years; 38.5% were female; mean time since diagnosis was 10.8 years (standard deviation [SD] 7.5); 88.5% switched from ravulizumab and 11.5% from eculizumab. BL mean (SD) Hb and lactate dehydrogenase (LDH) were 11.87 g/dL (1.32) and 226.8 U/L (69.05), respectively; 38.5% of pts had BL Hb ≥12 g/dL.

Adjusted mean (95% CI) ΔBL in Hb was +2.01 g/dL (1.74, 2.29) and statistically significant (P<0.0001 for both noninferiority and superiority); subgroup results for BL Hb <12/≥12 g/dL were +2.37 (2.01, 2.74) and +1.44 (1.04, 1.84) g/dL, respectively. Mean Hb at 24 weeks was 13.88 g/dL (SD 1.27; Figure). No pts required RBCTs between Day 1 and 168. Proportion of pts with Hb ≥12 g/dL between Day 126 and 168 was 92.7% (95% CI 84.6, 98.1). Adjusted mean ΔBL in absolute reticulocyte count (ARC) was −89.19 × 109/L (95% CI −95.47, −82.92). Mean ARC at 24 weeks was 60.40 × 109/L (SD 22.36; Figure). Geometric adjusted mean ratio of LDH vs BL was 0.99 (95% CI 0.93, 1.04). Adjusted mean (95% CI) ΔBL in FACIT-Fatigue was +4.29 (1.74, 6.85) and in TSQM-9 effectiveness, convenience and global satisfaction was +12.54 (5.58, 19.49), +23.86 (17.62, 30.10) and +18.53 (12.87, 24.19), respectively. One pt discontinued iptacopan because of a treatment-emergent adverse event (TEAE) of non-serious palpitations suspected to be related to iptacopan. Two pts had serious TEAEs (bacterial pneumonia; pyrexia with traumatic subdural hematoma); none were reported as related to iptacopan. Headache (17.3% of pts), diarrhea, nausea and nasopharyngitis (11.5% each) were the most frequent TEAEs and the infections system organ class had the most pts with TEAEs (42.3%). No pts had clinical breakthrough hemolysis, major adverse vascular events or died

APPULSE-PNH met its primary and key secondary objectives. Oral iptacopan monotherapy led to clinically meaningful increases in Hb, Hb normalization in almost all pts, transfusion avoidance in all pts and reductions in ARC. Pts also reported improvements in fatigue and treatment satisfaction. Iptacopan was well tolerated with no new safety findings. Iptacopan is a potentially practice-changing treatment that may become a preferred outpatient option for pts with PNH.

OBTAINING INSIGHTS ON PNH MANAGEMENT WITH IPTACOPAN IN EVERYDAY CLINICAL PRACTICE: A RESEARCH COLLABORATION WITH THE IPIG PNH REGISTRY

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder marked by intravascular hemolysis and thrombosis. Despite progress, patients often face persistent anemia and need blood transfusions. Phase 3 trials with iptacopan, an oral factor B inhibitor, show hemoglobin improvement, reduced blood transfusions, and improvements in fatigue while controlling hemolysis. It compares favorably to other complement inhibitors (CI) like eculizumab and ravulizumab. However, there are limited data on iptacopan in routine clinical care.

The IPIG PNH Registry, established in 2024, tracks disease evolution, patient outcomes, health resource use, long-term safety, and real-world treatment impacts, including iptacopan. A dedicated drug silo within the Registry collects data from patients using iptacopan in routine care. This research collaboration aims to generate valuable insights into patient demographics, disease manifestation and management, hematological and biochemical treatment responses, health resource utilization, and clinical events and outcomes for patients with PNH initiating iptacopan in routine clinical care. Additionally, it will collect information on any safety events and pregnancies occurring during treatment.

Data from the IPIG PNH Registry, a global, prospective, multi-center observational registry (NCT06524726), are collected starting from July 2024. As of February 2025, 328 patients are enrolled, with 21 on iptacopan. The analyses include adults (≥18 years) clinically diagnosed with PNH, whether CI-naïve or experienced, and receiving iptacopan. Data from at least 200 patients will be collected in 10 countries, with planned interim analyses and a final report scheduled for 2030. Initial visit measurements, along with 6-monthly follow-up assessments, encompass demographic information, laboratory data, clinical symptoms, clinical events and outcomes, health resources, pregnancy and safety, and self-administered quality of life questionnaires. Patients receive care as defined by their physician and are followed until the earliest of discontinuation, death, consent withdrawal, or study end. This research collaboration is advancing research and innovation in PNH. Recruiting patients for PNH studies is challenging due to its rarity. The IPIG PNH Registry supports collaborative efforts to gather real-world data on patient outcomes and treatment efficacy. By enrolling eligible patients, it enhances our understanding of PNH management and generates additional knowledge regarding the long-term safety and effectiveness of iptacopan in routine clinical practice, including its impact on special populations such as pregnant women.

PROPHYLAXIS AND MANAGEMENT OF THROMBOEMBOLISM IN PNH PATIENTS: AN ITALIAN SURVEY

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, non-neoplastic hematopoietic stem cell disorder characterized by complement-mediated hemolysis, bone marrow failure, and a increase thromboembolic risk. The acquired thrombophilia state is responsible for life-threatening venous thrombosis, arising in typical and often atypical sites, with up to 67% of mortality. Complement inhibitors (CI) have significantly improved the natural history of PNH by controlling hemolysis and reducing thrombotic risk. However, no consensus is available for management and prophylaxis of thromboembolism in the CI and new anticoagulants (AC) drugs era. The aim of this study run by Anna Paola Iori et al. is to gain an overview of the national policy on the management of thrombotic complications, a specific survey was designed addressing the key issues in the management of prophylaxis and treatment of thrombotic events. The survey consisted of 3 major items: primary and secondary prophylaxis, and management of thrombotic risk during BTH. The questionnaire was submitted to 23 Italian Hub Centers (IHC).

Total number of patients followed in the participating centers is 277, with a median number of patients per center of 6 (range 1-40). The questionnaire and the results are detailed in Figure 1. Overall, the first two domains showed high heterogeneity. Regarding untreated PNH, about 1/3 of responders each advised primary prophylaxis in all patients, in selected patients with other risk factors for thrombosis, and in no patients. Preferred drugs were vitamin K antagonists (VKA) and low molecular weight heparin (LMWH), and those advising prophylaxis would discontinue it once CI are started. Regarding secondary prophylaxis, VKA are the most used drugs, followed by LMWH and direct anticoagulants, and 3/4 of respondents would continue it indefinitely even after CI start. Finally, high uncertainty emerges regarding prophylaxis during BTH, with most respondents considering it (either always, for massive BTH only, or in selected cases) and LMWH being the preferred choice.

This Italian survey emphasizes the lack of a common policy in the prophylaxis and management of thromboembolism in PNH patients, highlighting the need for future harmonization.

THE DAILY IMPACT OF FATIGUE IN PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA (PNH): AN ETHNOGRAPHIC STUDY

PNH is a rare haematological condition characterised by destruction of red blood cells by the complement system; fatigue is a key symptom that has significant impact on patient quality of life. Fatigue associated with PNH is often under recognised despite evidence to suggest 75-89% of C5 complement inhibitors (C5i) recipients still experience symptoms of fatigue.  At the time of research, C5is were the standard treatment for PNH. Patient testimony around daily fatigue experience in PNH is limited. This study aimed to explore the daily impact of fatigue on patients treated for PNH with C5 inhibitors; how patients recognise, manage and communicate fatigue, with a focus on the deeper emotional / psychological aspects of fatigue.

This primary, qualitative, adapted ethnographic study recruited adult patients diagnosed with PNH for ≥2 years and with a FACIT-fatigue score of ≤36 (vs. general population score: 43.5), treated at the time of survey with a C5i for ≥6 months. A series of adapted ethnography tasks were completed over 2 weeks. Each patient committed 1-2 hours total. An online bulletin board platform was used for data collection, allowing private reflections, group discussion and probing from moderators. Tasks included survey questions and qualitative exploration of themes through videos, images and text responses. Core topics comprised: treatment experience with C5is; effect of fatigue on daily functioning; and exploration of HCP relationships and communication.
32 patients (Germany n=1, Spain n=2, China n=15, Japan n=5, Canada n=4, Brazil n=5) participated in the study. All experienced fatigue, with a mean FACIT-fatigue score of 24 (a score <30 suggests extreme fatigue). Fatigue was rated as one of the most bothersome symptoms, with 91% of respondents selecting it in the top 3; 79% reported feeling burdened by fatigue daily.

Almost all (97%) struggled with basic physical activity due to fatigue e.g. walking, climbing stairs, self-care. Brain fog and mental exhaustion from fatigue was reported to impact 84% of patients' work lives. 75% reported fatigue impacting family life, particularly childcare responsibilities (38%) and an increased need for peer support (34%). Fatigue also affected social activities, such as ability to maintain and develop hobbies (31%) and attend social events (22%). Fatigue also has a significant negative impact on patients' emotional / mental wellbeing. Feelings of anxiety and depression (31%), isolation (25%), hopelessness (19%) and guilt (19%) were most-frequently mentioned. Though most (94%) respondents had discussed fatigue with a physician, 41% felt their doctor was not concerned. The perceived reason for lack of concern from an HCP was other symptoms of PNH being prioritized, lack of alternative treatments and fatigue being an expected symptom of PNH. When asked about new treatments, 78% stated that fatigue improvement would be an extremely important consideration.

This is the first ethnographic study exploring in-depth the symptoms, feelings and impacts that PNH has on patients. They described that fatigue remains a major challenge despite management with C5is. Fatigue impacts all aspects of patients' lives, including physical health, work, social life, and emotional wellbeing. Further research is needed to ensure newer treatment options for PNH improve fatigue.

SYSTEMATIC MAPPING OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA RESOURCES: IDENTIFYING GAPS IN CLINICAL EDUCATION TOOLS TO IMPROVE DIAGNOSIS AND PATIENT CARE

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare, life-threatening hematologic disorder caused by dysregulated complement system, leading to chronic intravascular haemolysis, extravascular haemolysis and a high risk of thrombotic complications. Due to its non-specific presentation and overlap with other haematologic conditions, diagnostic delays are common. Low awareness of PNH among healthcare professionals (HCPs) contributes to these challenges, highlighting the need for enhanced education tools to support recognition, diagnosis and disease management. Here, the authors aim to present results from a systematic mapping review to evaluate PNH resources for HCPs and patients.
A systematic mapping review was conducted to assess resources for PNH, including academic publications, clinical guidelines, patient education materials and HCP training tools related to diagnosis, management and education. Resources were sorted into 1 of 4 categories (pre-diagnosis, diagnosis, treatment, and disease management/progression) based on the target audience, content focus and applicability across each stage of the patient journey.

A total of 114 PNH resources were identified and categorised (Figure 1). Pre-diagnosis resources (n=25) primarily focused on raising awareness of early symptoms and guiding patients toward expert HCPs. Diagnosis resources (n=22) centred on understanding laboratory tests and the challenges of achieving a timely diagnosis. Treatment resources (n=32) provided information on available therapies, mechanisms of action and access to care. Disease management and progression resources (n=35) focused on quality of life and complications associated with chronic PNH.  Although public awareness campaigns like March for Marrow, PNH Awareness Week, and Rare Disease Day exist, insufficient frontline HCP education contributes to diagnostic delays. While resources like Find a Specialist connect patients to experts, there is a lack of clinical education and diagnostic tools for HCPs to recognise symptoms of PNH, and a there is gap in dissemination and accessibility of existing resources.

These results provide data on the utility of targeted symptom guides and CME/CE modules to improve early recognition, referrals and diagnosis of PNH. The PNH resource review indicates that psychosocial support networks such as Better Living with PNH and PNH support groups provide valuable resources. The expanding treatment landscape, including clinical trials, can be overwhelming for patients and HCPs. Our systematic mapping review indicates that, despite the variety of available treatments and resources for PNH, there is a lack of shared decision-making tools to facilitate meaningful discussions and optimal care planning. The PNH diagnostic journey is long and challenging, with disease symptoms, treatment regimens and the psychological distress of patients and caregivers impacting daily life and quality of life. Despite the availability of 114 resources for PNH, this systematic mapping review highlights critical gaps in existing education tools exacerbated by the rarity and complexity of PNH, particularly in relation to early diagnosis and quality of patient care, and opportunities to improve dissemination. Addressing these gaps through targeted clinical sources and educational and emotional wellbeing support programs, as well as decision-support tools, could improve early recognition, treatment optimisation and holistic disease management for patients with PNH.

 

A SINGLE CENTER REAL-WORLD ANALYSIS: CLINICAL CHARACTERISTICS AND PREDICTION OF THROMBOSIS RISK IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of hematopoietic stem cells,which characterized by hemolytic anemia, bone marrow failure, thrombosis, and multiple organ failure. High-risk thrombosis is one of the characteristics and the main causes of the high mortality rate in PNH patients. According to statistics, cases of death caused by thrombosis account for approximately 40% to 67%. Before diagnosis, about 40% of patients have experienced a thrombotic event, and during the process of disease diagnosis and treatment, 29%-44% of patients have experienced at least one thrombotic event. Therefore, timely and accurate assessment of the risk of thrombosis is of great significance to clinicians.

The aim of this study is to identify the risk factors for thrombosis in PNH patients and predict thromboembolic events.
A total of 220 patients with PNH who were treated in the Department of Hematology of Tianjin Medical University General Hospital from February 1, 2014, to September 30, 2024, were included in the study. Among them, there were 125 male patients and 95 female patients. The clinical data of the patients were collected, and the occurrence of thrombosis was determined. Variables with non-zero coefficients were screened through LASSO regression. Risk factors for thrombosis were determined by multivariate stepwise Logistic regression, and dynamic/static nomogram models were constructed. A total of 220 patients with PNH were analyzed. Among them, 129 cases (58.64%) were the classical PNH, and 84 cases (38.18%) were bone marrow failure/PNH (BMF/PNH). The main clinical manifestations were fatigue, hemoglobinuria, dizziness and palpitations. Some patients had symptoms such as abdominal pain, dysphagia, dyspnea, erectile dysfunction and chest pain. By the end of the observation period, 19.09%(42/220) patients had thromboembolic events. A total of 74 thromboembolic events occurred cumulatively, including 28 arterial events (37.84%), mainly cerebral artery and coronary artery embolism; and 46 venous events (62.16%), mainly in the portal venous system. We included 34 clinical indices of the patients in LASSO regression analysis. After dimensionality reduction, 8 variables with non-zero coefficient features were screened out, namely red blood cell count (RBC), albumin (ALB), fibrinogen (FIB), D-dimer, type II clone erythrocytes, PNH granulocytes, whether glucocorticoids were used in the treatment, and whether there was a MUC4 gene mutation. The variables screened by the LASSO regression were further included in the multivariate bidirectional stepwise Logistic regression analysis. The results showed that ALB (odds ratio [OR]=0.85), FIB (OR=0.51), D-dimer (OR=1.01), type II clone erythrocytes (OR=1.04), PNH granulocytes (OR=1.04), the use of glucocorticoids in the treatment (OR=6.39), and the presence of a MUC4 gene mutation (OR=35.65) were risk factors for thrombosis in PNH patients(p<0.05).

A decreased plasma albumin and fibrinogen level, an increased D-dimer level, an increased proportion of type II red blood cell clones and granulocytic PNH clones, the use of glucocorticoids, and MUC4 mutations are risk factors for the occurrence of thrombosis in PNH patients. Early identification and timely anticoagulation can prevent the occurrence of thrombosis in PNH patients.

INDIRECT TREATMENT COMPARISON OF IPTACOPAN VS. PEGCETACOPLAN IN COMPLEMENT INHIBITOR NAÏVE PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATIENTS

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired genetic disorder characterized by complement-mediated hemolysis and subsequent anemia. Two recently approved proximal monotherapies are: iptacopan, a factor B inhibitor; first oral monotherapy, and pegcetacoplan, a complement 3 inhibitor; administered as subcutaneous infusion. These drugs have demonstrated efficacy in their respective trials in PNH patients naïve to complement therapy, however, have not been studied in a head-to-head (H2H) clinical trial.

The aim of this study is to assess the comparative efficacy of iptacopan vs pegcetacoplan in PNH patients naïve to complement therapy using an indirect treatment comparison (ITC).

A systematic literature review, conducted with searches until April 20, 2023, identified two phase III clinical trials in the target population: APPOINT-PNH (NCT04820530) a single-arm trial of iptacopan; with available individual patient data (IPD), and PRINCE (NCT04085601), a randomized controlled trial of pegcetacoplan vs supportive care only (excluding complement inhibitors), with published summary data. The key eligibility criteria for the trials were generally similar with some differences such as, in hemoglobin (Hb; g/dL) levels (<10 in APPOINT; <12 in females and <13.5 in males in PRINCE). An unanchored simulated treatment comparison (STC) was conducted. STC is an established method allowing population adjustment of the IPD from one study to the summary level data of the comparator. A regression model was applied to IPD from the APPOINT trial and the fitted model was used to simulate the effect of iptacopan in the population studied in PRINCE. Selected baseline characteristics (age, sex, transfusion avoidance, history of aplastic anemia, and baseline lactate dehydrogenase [LDH]) identified as potential treatment modifiers were included as covariates in the regression model. The outcomes considered for this analysis were change from baseline (CFB) in Hb, CFB in LDH, and transfusion rate. Results were reported using point estimates (mean difference; rate ratio) and 95% confidence intervals (CIs) for each analysis. Nominal significance was ascertained using a two-tailed P-value of <0.05.

The analysis included a sample size of 40 for iptacopan and 35 for pegcetacoplan, consistent with their respective trial populations. The predicted outcome for iptacopan for mean (standard deviation [SD]) CFB in Hb was 4.4 (0.3), and the published mean (SD) CFB in Hb for pegcetacoplan was 2.9 (0.4). This resulted in a significant mean difference favoring iptacopan vs pegcetacoplan: 1.47 (95% CI: 0.10, 2.83). The predicted mean (SD) CFB in LDH for iptacopan was -1,851.5 (17.7) U/L, and the published mean (SD) CFB for pegcetacoplan was -1,870.5 (101.0) U/L, resulting in a mean difference of 19.04 (-0.81, 38.89) (Table). The predicted transfusion rate (95% CI) assessed per patient-month for iptacopan was 0.0268 (0.0004, 1.7886) and that for pegcetacoplan was 0.154 (0.139, 0.171). This resulted in a rate ratio (95% CI) favoring iptacopan vs pegcetacoplan of 0.1742 (0.1333, 0.2275) (Table).

In the absence of a H2H trial, this ITC suggests that patients on iptacopan might have significantly higher increase in Hb and lower transfusion rates, with similar effectiveness in LDH control, when compared with pegcetacoplan. These findings should be interpreted within the framework of STC, with its strengths and limitations.

NETWORK META-ANALYSIS COMPARING THE EFFICACY OF DIFFERENT COMPLEMENT PATHWAY INHIBITORS FOR THE TREATMENT OF PAROXYSMAL NOCTURNAL HEMATURIA

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, complement-mediated hemolytic anemia. Somatic mutations of the PIGA gene lead to dysregulated complement activity, causing complement-driven erythrocyte lysis and predisposition for venous and arterial thrombosis. The introduction of terminal complement inhibitors eculizumab and ravulizumab have markedly improved the natural history of the disease, with a median survival now matching that of age-matched controls. However, variations in hematological responses persist due to factors including C3-mediated extravascular hemolysis. In order to overcome this residual hemolysis, novel C5 inhibitors and proximal complement inhibitors have recently been developed and approved for use in the clinic. However, no head-to-head comparison of these novel complement inhibitors has been performed to date. 

The authors performed a systematic review and network meta-analysis comparing the efficacy of four new complement inhibitors: pegcetacoplan, iptacopan, danicopan, and crovalimab, to aid in the decision-making process regarding the optimal drug choice for the treatment of PNH.
We performed a systematic literature review and network meta-analysis utilizing data from three databases: PubMed, Web of Science, and Cochrane Library. Data were systematically searched using relevant keywords from inception until July 2024. Efficacy outcomes included hemolysis markers such as hemoglobin (Hb), LDH level, transfusion independence, and change in fatigue levels. Network meta-analysis was performed using R version 4.4.2 and packages jrags and gemtc.

Of the 1,175 initially identified papers, six encompassing five different clinical trials (ALPHA, APPLY-PNH, COMMODORE 1, COMMODORE 2, and PEGASUS) were included in the systematic review. Of the five trials, COMMODORE 2 was the only trial performed as a first-line treatment, and the patients included in the study tended to be younger with higher baseline LDH values. Clinical characteristics of the patients included in the other four studies were relatively similar, and therefore, a network meta-analysis to indirectly compare the efficacy of the four drugs was performed using these four studies. The proportion of patients with greater than 2 g/dL improvement in the Hb level was significantly higher with proximal complement inhibitors than eculizumab/ravulizumab. The trend for superior outcomes with proximal complement inhibitors compared to eculizumab/ravulizumab was persistent for other efficacy measures, but the difference was not statistically significant. Also, there was no significant difference in the efficacy among proximal complement inhibitors. Regarding ranking between different complement inhibitors, iptacopan ranked first in two of the four outcome measures (greater than 2 g/dL improvement in Hb levels and transfusion avoidance). In contrast, pegcetacoplan ranked first in the remaining two measures (mean change in Hb level and improvement in fatigue score). 

Proximal complement inhibitors are more effective than eculizumab/ravulizumab in controlling anemia-related symptoms of PNH. While there is no significant difference between novel proximal complement inhibitors, our results suggest that iptacopan or pegcetacoplan may be the preferred drug. Additional factors such as route and frequency of drug administration should be taken into consideration when selecting the optimal treatment choice for the patients. 

REAL-WORLD OUTCOMES AND CLINICAL BURDEN OF PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterized by complement-mediated hemolysis. The most common manifestations of PNH include anemia, fatigue and dyspnea. Current treatments include complement inhibitors (Ci) targeting complement 5 (C5), complement 3 (C3), and factor B or D of the alternative complement pathway. Despite treatment of PNH patients with Ci led to improved clinical outcomes, patients continue to experience significant clinical burden. This multinational, real-world study aimed to understand the clinical profile and burden in PNH patients.

Data were drawn from the Adelphi PNH Disease Specific Programme™ Wave II, a real-world, cross-sectional survey of physicians and their PNH patients, conducted in December 2023 - May 2024, across France, Germany, Italy, Spain and United Kingdom. Physicians completed patient record forms which included data on patient demographics, clinical signs and symptoms, treatments, laboratory parameters (hemoglobin [Hb], lactate dehydrogenase [LDH]), and blood transfusions, for up to next 10 consecutively consulting patients. Data were analyzed by country and pooled using descriptive statistics with no imputation for missing values.
A total of 65 physicians provided data on 343 patients. Median (interquartile range [IQR]) age at the time of the survey was 48.0 (35.0, 60.0) years, 58% patients were male, and 48% (n=166) had at least one other concomitant condition (Table). Among them 33% had PNH related comorbidities (aplastic anemia [23%], myelodysplastic syndrome [10%] and myelofibrosis [1%]) and 80% had non-PNH related concomitant conditions (e.g. diabetes, anxiety, depression etc.). Median (IQR) age at diagnosis (n = 338) was 42.4 (31.7, 56.3) years, and time since diagnosis was 2.0 (0.9, 4.8) years. Physicians reported that PNH was primarily classical (for 72% of cases), subclinical (15%) and with bone marrow failure syndrome (12%). Among all patients (n = 343), 77% (n =265) were on any Ci (C5i [91%] and C3i [9%]). The median (IQR) treatment duration on any Ci was 1.3 (0.6, 2.5) years (C5i: 1.5 [0.6, 2.7] and C3i 0.8 [0.4, 1.0]). Data by country can be found in Table. Out of 264 patients prescribed with Ci medication at survey, 64% of C5i and 54% of C3i patients had suboptimal Hb levels (<12 g/dL) (Table). Median (IQR) LDH level (U/L) of patients on C5i and C3i was 250.0 (203.0, 338.5) and 220.0 (190.0, 345.0) respectively. At time of survey, 73% of C5i- and 83% of C3i-treated patients experienced PNH symptoms with most common being anemia (C5i, 47%; C3i, 29%), and fatigue (C5i, 42%; C3i, 46%). Among patients prescribed Ci with treatment duration data (n = 260), 60% were on treatment for ≥12 months. Of these, 18% had at least one transfusion with a mean (SD) of 3.6 (4.3) and 17% experienced a breakthrough hemolysis with a mean (SD) of 1.7 (1.0) events in the past 12 months.

In this real-world study, despite receiving Ci, 64% of C5i- and 54% C3i-treated patients had suboptimal Hb (<12 g/dL) and continued to experience symptoms of fatigue and anemia, and some still require blood transfusions. These results indicate an unmet need for effective and safe treatments which can improve clinical outcomes and alleviate symptoms.