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1
Duran, Munevver N., Zehra Tombul, Mutlu Mete, et al. "Predicting Extravascular Hemolysis in Paroxysmal Nocturnal Hemoglobinuria." Blood 144, Supplement 1 (2024): 2695. https://doi.org/10.1182/blood-2024-204213.
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Introduction Paroxysmal Nocturnal Hemoglobinuria (PNH) is a life-threatening blood disorder characterized by the destruction of red blood cells due to complement system dysregulation. The advent of C5 complement inhibitors has markedly improved the outlook for PNH patients by mitigating intravascular hemolytic crises and thrombotic events. However, many patients undergoing C5-inhibitor treatment experience C3-mediated extravascular hemolysis (EVH), which can lead to transfusion dependence, lower quality of life, and poorer health outcomes. The development of proximal complement inhibitors has heightened the need to identify patients at high risk for EVH resulting from C5 inhibitor therapy. Predictive models that identify these high-risk PNH patients could enable personalized, physician-supervised treatment selection, improving clinical outcomes and reducing healthcare costs. We describe a machine learning model, trained on demographic, laboratory, and Next-Generation Sequencing (NGS) data, designed to predict the risk of EVH in PNH patients. Methods We analyzed the medical records of 172 PNH patients treated between 2000 and 2022 at the University of Texas Southwestern and Cleveland Clinic Foundation. The dataset included clinical, laboratory, and NGS sequencing information, with specific clinical variables such as the type and duration of complement inhibitor(s) used, PNH clone size and distribution, EVH occurrence, antecedent aplastic anemia, and laboratory markers of hemolysis. Laboratory markers included lactate dehydrogenase (LDH), hemoglobin, absolute reticulocyte count and percentage, total bilirubin, d-dimer, AST, ALT, direct antiglobulin test (DAT), WBC, MCV, and platelet count. Missing data were imputed using the K-Nearest Neighbors algorithm (K=10). Feature selection through a Random Forest algorithm identified 23 significant clinical markers. A 5-layer multilayer perceptron classification algorithm trained using Leave-One-Out Cross Validation (LOOCV), achieved 87% sensitivity, 75% specificity, and an Area Under the Curve (AUC) of 0.80. Results Out of the 172 patients, 104 started on C5 complement inhibitors, while one began on a C3 inhibitor; eventually, nine were on a C3 inhibitor. About 26% of patients (n=27) were tested for EVH based on persistent anemia, with 15 testing positive for C3 complement activation at DAT evaluation. Of these, 71% were treated with eculizumab, and 28% with ravulizumab. Significant differences in clinical markers, such as Type II RBC levels (predictive score of 0.72), hemoglobin levels (predictive score of 0.42), LDH levels (predictive score of 0.50), and reticulocyte counts (predictive score of 0.46), were observed between EVH-positive and EVH-negative patients. Discussion Our findings are promising, demonstrating a machine learning model capable of predicting EVH with high accuracy. Given the recent approval of C3 and factor B inhibitors and ongoing development of proximal complement inhibitors, predicting EVH in PNH patients on C5 inhibitor therapy is increasingly relevant. Our model represents a significant advancement in identifying the risk of EVH at the time of diagnosis using accessible clinical variables. This predictive capability could enhance treatment monitoring, personalize treatment strategies based on patient risk profiles, and reduce healthcare costs. Future retrospective cohort studies to validate our model on patient data from other institutions would be valuable.
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Swathi., D. 1* Ramesh Kumar Reddy. P. 1. Dr. R. Siddarama2. "APLASTIC ANEMIA WITH SUB CONJUNCTIVAL HAEMORRHAGE AND PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA: A RARE CASE REPORT." Indo American Journal of Pharmaceutical Sciences 047, no. 07 (2017): 1952–55. https://doi.org/10.5281/zenodo.832437.
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This Case report describes a case of idiopathic acquired aplastic anemia in an 18-year-old male patient with petechial rash, sub conjunctival haemorrhage and paroxysmal nocturnal haemoglobinuria. Patient was treated with elthrombopag olamine- 50mg and cyclosporine- 200mg these two drugs are showing good response in most of the patients with Aplastic anemia in the absence of human leucocytes antigen (HLA) matched sibling donor. In some studies good response was shown for elthrombopag olamine 150mg/day. In this patient only 50mg of elthrombopag olamine is given, patient was died because of the febrile neutropenia. The dose adjustment of drugs in this patient was necessary; this is the responsibility of clinical pharmacist by giving suggestions to physician to adjust the doses as per the patient response towards the therapy. Keywords: Aplastic anaemia, proximal nocturnal hemoglobinuria, Elthrombopag olamine, subconjuctival haemorrhage
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Peixoto, Vanda, Ana Carneiro, Fernanda Trigo, Mónica Vieira, and Cristina Prudêncio. "Paroxysmal Nocturnal Hemoglobinuria: A Case Report in a Pandemic Environment." Reports 6, no. 3 (2023): 42. http://dx.doi.org/10.3390/reports6030042.
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Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, rare, complement-mediated hemolytic anemia. PNH can be associated with marrow failure and thrombophilia. We present a clinical report of splenic vein thrombosis in a patient with classic PNH. A 41-year-old male with classic PNH, naïve to complement inhibitor therapy, developed splenic vein thrombosis as a major adverse effect after vaccination protocol to prevent meningococcal disease. We also report anticoagulant and eculizumab treatment outcomes. In PNH patients, vaccination should be monitored to prevent major outcome events, like vaccine-induced thrombosis. Eculizumab proves effective for treating intravascular hemolysis and preventing more thrombotic events. The potential protective role of eculizumab on controlling complement activity and consequent inflammation may help the patient to not experience breakthrough hemolysis when infected with SARS-CoV-2. Extravascular hemolysis remains present, but new molecules are being studied to inhibit proximal complement and there is a good health prospective for PNH patients.
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Wong, Raymond S. M. "Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria." Therapeutic Advances in Hematology 13 (January 2022): 204062072211146. http://dx.doi.org/10.1177/20406207221114673.
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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by complement-mediated hemolysis, thrombosis, and various degrees of bone marrow dysfunction. Until recently, C5 inhibition with eculizumab or ravulizumab represented the only therapies approved for patients with PNH by the United States Food and Drug Administration (US FDA). Although C5-inhibitors reduce PNH-related signs and symptoms, many patients continue to exhibit persistent anemia and require frequent blood transfusions. In May 2021, pegcetacoplan became the third US FDA-approved treatment for adults with PNH, and the first to target C3, a complement component upstream of C5. The novel strategy of inhibiting proximal complement activity with pegcetacoplan controls C5-mediated intravascular hemolysis and prevents C3-mediated extravascular hemolysis. Here, we review the results from multiple pegcetacoplan clinical studies on the efficacy and safety of pegcetacoplan treatment in adults with PNH. This review summarizes findings from three studies in complement-inhibitor-naïve patients with PNH (PADDOCK [phase Ib], PALOMINO [phase IIa], PRINCE [phase III; pegcetacoplan versus standard treatment excluding complement-inhibitors]), and one phase III study (PEGASUS) that compared eculizumab to pegcetacoplan in patients who remained anemic (hemoglobin levels < 10.5 g/dL) despite stable eculizumab treatment (⩾3 months). These studies found that pegcetacoplan contributed to superior improvements in primary and secondary endpoints related to hemoglobin levels and other hematologic parameters and provided effective management of anemia and anemia-related complications (i.e. transfusion burden, reticulocyte production, and fatigue). Furthermore, we summarize results from the 32-week open-label period from the PEGASUS trial, which confirmed the long-term safety and durable efficacy of pegcetacoplan as demonstrated by sustained improvements in clinical and hematologic outcomes in pegcetacoplan-treated patients. Pegcetacoplan is approved for the treatment of adults with PNH in the United States (Empaveli™) and for adult patients who remain anemic after at least 3 months of stable C5-inhibitor therapy in the European Union (Aspaveli®) and Australia (Empaveli; also approved for patients intolerant to C5-inhibitors).
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Vallejo, Carlos, Santiago Bonanad Boix, Fernando Carnicero, et al. "Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Pegcetacoplan: Real Life Experience." Blood 142, Supplement 1 (2023): 5653. http://dx.doi.org/10.1182/blood-2023-185570.
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Introduction: C5 inhibitors (C5i) treatment has dramatically improved the management of intravascular hemolysis (IVH) in PNH patients. However, a significant proportion of patients remain anemic due to suboptimal control of IVH and the development of extravascular hemolysis (EVH), consequence of C5i treatment. Pegcetacoplan (PEG) is the first proximal inhibitor of the complement system, through the inhibition of C3, allowing to control both IVH and EVH. PEG has recently been marketed in Spain for use in adult PNH patients who remain anemic after treatment with an C5i for at least 3 months. The objective of this work is to analyze the response of the first patients treated with PEG in real life in Spain. Patients and methods: clinical and analytical variables were collected from a series of 10 patients diagnosed with PNH who received treatment with PEG through an early access program. PEG was self-administered subcutaneously at 1080 mg twice a week. See Table 1. Transfusion needs and the adverse effects that occurred were also collected. Results: median (range) duration of treatment with PEG at the time of the analysis was 4 (2-8) months. Hemoglobin (Hb) values increased a median of 2.4 g/dL after PEG treatment. This improvement was rapidly observed since the beginning of the treatment (median increase at 1 week was 1.3 g/dL and at 2 weeks 2.4 g/dL). All patients reached Hb levels of &gt;8 g/dL, 80% &gt;10 g/dL and 40% &gt;12 g/dL. An increased in Hb &gt;2 g/dL was observed in 60% of the patients. Median values of parameters of hemolysis (absolute reticulocyte counts, bilirubin, LDH) became normal. See Table 2. The direct antiglobulin test turned into negative in all positive cases pre-PEG (4 out of 4). No patient suffered from acute hemolytic events, thrombosis, or required PRBC transfusion once PEG had been initiated. On a 5-point scale (0: nothing; 5: very much), subjective improvement of patient quality of life and physician satisfaction were 4 (3-5), and 5 (3-5) [median (range)]. PEG-related adverse events were just reported in one patient (10%): mild post-infusion nausea. At the end of the analysis, all patients continue on PEG. Conclusions: the results observed in the first patients treated with PEG in real life in Spain, although with a limited follow-up, confirm those reported in phase 3 clinical trials, with significant improvement in the Hb levels and hemolysis parameters, which results in transfusion independence. PEG was also shown to act quickly from the start of treatment, to significantly improve quality of life, and to present an excellent safety profile. PEG, the first approved proximal complement inhibitor, can therefore be considered as a relevant therapeutic option in the current management of PNH.
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Ahmed, Arooj, Mark Orland, Praveena Thiagarajan, et al. "A Real-Life Experience of Iptacopan in Paroxysmal Nocturnal Hemoglobinuria." Blood 144, Supplement 1 (2024): 5695. https://doi.org/10.1182/blood-2024-211788.
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The availability of complement inhibitors has dramatically changed the management of PNH. The longest experience exists with C5 inhibitors. Introduction of C3 blockade allowed also to overcome extravascular hemolysis in patients with break through hemolysis. Parenteral treatment options like complement protein C5 and C3 inhibitors, thus, became the mainstay therapeutic options in PNH. Recently, the PNH therapeutic armamentarium has been expanded by the FDA approval of an oral factor B blocker, iptacopan administered as single agent to effectively control hemolysis in PNH. Obviously, there are many advantages and disadvantages of parenteral administration but oral agents may provide convenience. Established drugs have a track record of safety, but new proximal inhibitors may improve response rates in those who do not attain CR. Here, we provide a real-world experience with ipacopan to allow projections as to how expanded treatment options may affect the standard of care in this disease. We analyzed PNH patients who in course of their care inquired on the spectrum of therapies for PNH during routine outpatient follow up visits. Among 36 patients with a classical hemolytic PNH, a total of 30 patients were either started (N=4) or switched to iptacopan (N=26) from prior anti-complement treatment modalities. Of the currently treated patients, 16 were considered robust responders, while less than optimal hematologic improvement was present in 10 patients. Following consideration of the specific clinical situation and patient education as to the pros and cons of the newly available treatments, 30 patients elected to start iptacopan (26 treated and 4 treatment-naïve) of whom 10 are currently in the approval process. Of 17 responders on current complement blockers, 6 elected to remain on their current medication by personal preference of administration, impact on their wellbeing and blood counts, extensive track record of their current medication and concerns about difficulty with long-term coverage. The 4 complement-inhibitor “naïve” patients were offered 3 treatment options (pegcetacoplan, ravulizumab, iptacopan) and all selected iptacopan mainly due the convenience of oral medication. 2 of the 4 are currently in the approval process. The other 2 who received the drug showed improvement in Hgb from 10.5 and 11.9 to 11.3 and 12.1 respectively. Retic count and LDH also showed marked improvement indicating response within 3 months of starting iptacopan therapy. The previously treated patients who switched (n=26) had a median of 2 previous anti-complement inhibitors. Their therapy prior to switch included eculizumab (N=4), ravulizumab (N=13), pegcetacoplan (n=9). A prior diagnosis of aplastic anemia was present in 50% of our cohort. The median duration of the last regimen was 137 weeks. Out of 26 patients with prior treatment, 16 had satisfactory/excellent response and their switch was predicated on the convenience of oral administration or coverage issues. Their average Hgb was 12.8 g/dL at the start of treatment vs 13.9 g/dL in 3-months, retic 3.2 vs 2.4% after 3 months, LDH 278 vs 222 IU/dL prior to and at 3 months of therapy. In 10 patients prior therapy was not perceived as satisfactory as a main factor to initiate iptacopan. Average Hgb in these patients increased from 8.7 g/dL at the start of the treatment vs 9.8 g/dL in 3-months. There was also a significant decrease in LDH from 3-months after starting treatment 247 vs 196 IU/dL. Retic count significantly decreased from baseline 3-months after starting treatment (2.4±0.6 vs. 4.3±3.1%; p=0.042) at the start of the treatment. Overall, in all patients the PNH granulocyte clone size increased from before treatment (44±40) compared to 3 months after treatment (59±35; p=.03). The PNH erythrocytes increased from before treatment (31±5) compared to 3 months after treatment (45±34; p=0.22). Except for 2 instances of mildly increased lipids, no events like AE/thrombosis were reported. One patient developed community acquired pneumonia. Commonly reported side effect was intermittent mild headaches treatable with acetaminophen. No breakthrough hemolysis was observed, there were 2 instances of missing a dose without any complications. In conclusion, iptacopan provides a viable treatment option in those with suboptimal responses to current therapy and allows to achieve comparable results in patients otherwise well controlled by other complement inhibitors.
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Peffault de Latour, Régis, Jeffrey Szer, Koo Wilson, et al. "Anchored Indirect Treatment Comparison Finds Comparable Effects of Pegcetacoplan and Iptacopan in Paroxysmal Nocturnal Hemoglobinuria." Blood 144, Supplement 1 (2024): 7706. https://doi.org/10.1182/blood-2024-209712.
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Background Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired non-malignant hematological disorder characterized by thrombosis risk, high morbidity, and high symptom burden. This anchored indirect treatment comparison (ITC) evaluated the proximal complement inhibitors (Ci), pegcetacoplan (C3i) and iptacopan (factor B inhibitor) in C5i treatment-experienced patients with PNH. Methods Data obtained retrospectively from 2 pivotal clinical studies informed the ITC: patient-level data for pegcetacoplan from PEGASUS (NCT03500549) at 16 weeks, and digitalised published trial data for iptacopan from APPLY PNH (NCT04558918) at 24 weeks. The availability of a common reference C5i treatment group in both PEGASUS and APPLY PNH enabled the analyses. However, considering differences in data availability, study design, duration, and statistical methods between PEGASUS and APPLY PNH, a comparison of the primary endpoints measured in each study was not feasible. Hence, the ITC evaluated other select study endpoints including hemoglobin (Hb) levels, absolute reticulocyte count (ARC), lactate dehydrogenase (LDH) levels, and patient reported outcomes measured on Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale scores. The anchored ITC (Bucher method) was conducted based on mean changes from baseline (CFB) to randomized controlled period end (end of study, EOS; week 16 for pegcetacoplan and week 24 for iptacopan). Regression-based simulated treatment comparison (STC) assessed the robustness of results, with models selected based on the Bayesian information criterion. Results Baseline characteristics of patient populations in PEGASUS and APPLY PNH were broadly similar. Anchored ITC showed comparable outcomes (mean difference, [95% CI]; mean absolute values (SD) treatment arm vs control arm) in CFB to EOS across endpoints between pegcetacoplan vs C5i, and iptacopan vs C5i, respectively: Hb level-0.49 g/dL [-1.78 ,0.80], 54 (1.96) vs 8.58 (0.96) and 12.48 (1.12) vs 9.12 (1.42);ARC-34.41 109/L [-90.02, 21.21], 14 (26.63) vs 220.78 (88.73) and 70.96 (42.41) vs 176.19 (80.94);LDH level-115.16 U/L [-244.40, 14.07], 11 (78.05) vs 353.19 (477.50) and 270.96 (117.54) vs 275.96 (127.45);FACIT-Fatigue: 57 [-5.60, 12.73], 41.81 (9.61) vs 30.62 (11.76) and 43.08 (7.80) vs 31.04 (12.65). On safety versus pegcetacoplan, patients treated with iptacopan revealed significantly greater risk of headache, with no significant differences in other safety endpoints. STC analyses confirmed that point estimates and CI across all endpoints were consistent with results of the Bucher analyses. Conclusions This anchored ITC of the two proximal complement inhibitors, pegcetacoplan and iptacopan, used the best available trial data for the comparator treatments versus C5i standard of care, respectively. Our anchored ITC findings did not reveal significant differences between pegcetacoplan and iptacopan in clinical endpoints or patient-reported outcomes. Hence consideration of both, clinical and individualized patient-centered factors (including age, comorbidities, lifestyle needs, and administration preferences between pegcetacoplan long-acting subcutaneous or iptacopan short-acting oral), are clearly needed in treatment decision-making. In the absence of direct, head-to-head clinical trials, ITC provides robust comparative data on which to inform evidence-based medicine. The anchored ITC analytic approach has distinct advantages over unanchored comparisons, hence explaining the difference in findings by another previously presented ITC which did not use an anchored approach. One key strength is that the anchored ITC preserved the randomization feature of both trials while cancelling the impact of unbalanced prognostic factors, of which some are known and others unknown. A potential limitation was digitalisation of graphed data and imputation of standard deviation for mean CFB values, along with an assumption of normal distribution of the data.
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De Castro, Carlos, Phillip Scheinberg, Bing Han, et al. "Patient Experience Interviews with a Novel Treatment Iptacopan for Paroxysmal Nocturnal Hemoglobinuria." Blood 142, Supplement 1 (2023): 7339. http://dx.doi.org/10.1182/blood-2023-186840.
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Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal and complex disorder characterized by hemolytic anemia, thrombosis, smooth muscle dystonia, hemoglobinuria, and chronic kidney disease. Individuals with PNH experience severe and chronic fatigue, which can significantly impact their quality of life. While two anti-C5 antibody therapies have been approved for treating PNH (eculizumab and ravulizumab), the majority of patients who use these therapies still do not achieve normal hemoglobin levels. Iptacopan, the first oral proximal complement inhibitor developed to fill this critical need, has shown in two Phase III trials (APPLY-PNH [NCT04558918] and APPOINT PNH [NCT04820530]) to achieve a comprehensive control of hemolysis. As part of the trials, patient experience interviews were conducted with patients entering an iptacopan extension study (CLNP023C12001B) to explore their experience with the treatment. Objectives: To conduct patient experience interviews across 5 countries to understand and document how patients' PNH disease experience changed in response to treatment, the meaningfulness of any reported changes, patients' experience receiving the iptacopan treatment, patients' preference for iptacopan compared to other PNH treatments, and their satisfaction with treatment. Methodology: Patients were recruited by clinical sites in the United States, United Kingdom, France, Italy, and Germany enrolled in the iptacopan extension study. Patients enrolled in the iptacopan extension study were eligible to consent to and participate in an optional 30-minute qualitative interview. Interviews were conducted by independent, trained interviewers in the patient's local language. A semi-structured interview guide was used to ask patients open-ended questions to elicit spontaneous descriptions of their disease, and treatment experience, including satisfaction and preferences. Interviews were audio-recorded, transcribed verbatim, translated into English (if applicable), anonymized, coded, and then analyzed using qualitative data analytic methods. Results: Interviews were completed with 22 patients diagnosed with PNH across 5 countries. Following treatment with iptacopan, patients reported improvements in their PNH-related signs, symptoms, and impacts that they experienced before treatment. The most common symptoms that patients reported improvements in were fatigue (n=13/13, 100.0%), tiredness (n=11/12, 91.7%), and low energy (n=10/10, 100.0%). Patients most commonly reported their ability to work (n=5/8, 62.5%), ability to walk (n=4/8, 50.0%), and feelings of unhappiness (n=7/8, 87.5%) improved with treatment. Patients commented that these improvements in PNH-related signs, symptoms, and impacts were meaningful to them. When discussing their treatment experience with iptacopan, patients reported that they liked the convenience of the oral treatment (n=18, 81.8%), treatment efficacy (n=13, 59.1%), and reduced medical appointments (n=8, 36.4%). Additionally, patients described the oral administration as convenient (n=18, 81.8%) and the treatment schedule easy to follow (n=17, 77.3%). Some patients disliked the frequent treatment schedule in the trial (n=7, 31.8%). Of the 18 patients who were asked, all (n=18/18, 100.0%) reported they preferred iptacopan over previous PNH treatments overall, including eculizumab and ravulizumab (Table 1). Compared to previous anti-C5 PNH treatments, most patients preferred the iptacopan treatment administration (n=20/20, 100.0%) and treatment schedule (n=16/20, 80.0%). Overall, patients reported being very satisfied (n=14, 63.6%) or satisfied (n=8, 36.3%) with their iptacopan treatment experience (Table 2). Conclusion: These qualitative interviews provide evidence that patients were satisfied with their iptacopan treatment experience, and prefer iptacopan over other PNH treatments. Patients preferred iptacopan for the convenience of treatment administration and treatment schedule, the ease of following the treatment regimen, and liked the treatment for the oral administration, treatment efficacy, and reduced medical appointments. Additionally, this data demonstrates significant and meaningful improvement in patients' PNH-related signs, symptoms, and impacts with iptacopan.
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Ninomiya, Haruhiko, Naoshi Obara, Akiko Niiori-Onishi, et al. "Improvement of Renal Function by Long-Term Sustained Eculizumab Treatment in a Patient with Paroxysmal Nocturnal Hemoglobinuria." Case Reports in Hematology 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/673195.
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Chronic kidney disease (CKD) is one of the major manifestations of paroxysmal nocturnal hemoglobinuria (PNH). CKD in PNH is induced mainly by intravascular hemolysis of PNH-affected red blood cells (RBC) missing the glycosylphosphatidylinositol-anchored proteins with complement-regulatory activities, CD55 and CD59. CKD develops by heme absorption in the proximal tubules resulting in the interstitial deposition of iron in the kidneys. We administered eculizumab to a patient with PNH, who was one of 29 patients enrolled in the AEGIS clinical trial, an open-label study of eculizumab in Japan. The patient was complicated by stage 3 CKD with impaired estimated glomerular filtration rate (eGFR), at grade G3b, and had obvious proteinuria (2-3+, 1-2 g/day). In a two-year extension to the 12-week AEGIS study, eGFR improved significantly, and the eGFR has since been maintained at grade G2 without proteinuria by sustained eculizumab treatment (>6 years). Renal function improved and maintained by long-term sustained eculizumab treatment, presumably by clearance of iron from the kidney as well as inhibition of the production of anaphylatoxin C5a, even in advanced stages of CKD, is one of the benefits of eculizumab treatment in PNH.
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Horneff, Regina, Barbara Czech, Michael Yeh, and Elena Surova. "Three Years On: The Role of Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria (PNH) since Its Initial Approval." International Journal of Molecular Sciences 25, no. 16 (2024): 8698. http://dx.doi.org/10.3390/ijms25168698.
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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients’ quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.
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Anliker, Markus, Daniela Drees, Lorin Loacker, et al. "Upregulation of Checkpoint Ligand Programmed Death-Ligand 1 in Patients with Paroxysmal Nocturnal Hemoglobinuria Explained by Proximal Complement Activation." Journal of Immunology 208, no. 5 (2022): 1248–58. http://dx.doi.org/10.4049/jimmunol.2100031.
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Schrezenmeier, Hubert, Mohammed Mahdi, Christoph Gasteyger, and Cecile De Coster. "Breakthrough Hemolysis Events in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from Danicopan and Pegcetacoplan Trials." Blood 144, Supplement 1 (2024): 2694. https://doi.org/10.1182/blood-2024-203195.
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Background In the management of paroxysmal nocturnal hemoglobinuria (PNH), breakthrough intravascular hemolysis is indicative of insufficient disease control and may lead to significant morbidity and mortality. The terminal complement component 5 (C5) inhibitor (C5i) ravulizumab is the standard of care treatment for patients with PNH, where available. Danicopan is a first-in-class oral factor D inhibitor that targets the alternate pathway of the complement system. In the phase 3 ALPHA trial (NCT04469465), add-on danicopan therapy to background ravulizumab or eculizumab in patients with PNH and clinically significant extravascular hemolysis (csEVH) demonstrated efficacy and safety vs placebo at week 12 (Lee et al. Lancet Haematol 2023) and up to 24 weeks of the open-label extension (Kulasekararaj et al. Blood 2023). The efficacy and safety of pegcetacoplan, an approved proximal complement C3 inhibitor, has been evaluated in patients with PNH in the phase 3 PEGASUS trial (NCT03500549). However, severe hemolysis events have been reported in 24% of patients (Hillmen et al. N Engl J Med 2021; Kulasekararaj et al. N Engl J Med 2021), requiring further investigation. Objective To evaluate breakthrough hemolysis (BTH) events reported in the ALPHA and PEGASUS trials. Methods BTH data including pre- and post-event hemoglobin (Hb) and lactate dehydrogenase (LDH) levels, and actions taken were evaluated for up to 2.5 years for add-on danicopan and 3.0 years for pegcetacoplan. The most recent data cut for ALPHA (March 22, 2024) was used and data for PEGASUS were identified from the literature (Peffault de Latour et al. Lancet Haematol 2022; de Castro et al. Blood 2023; Peffault de Latour et al. Blood Adv 2024). Both trial designs have previously been reported (Lee et al. Lancet Haematol 2023; Hillmen et al. N Engl J Med 2021). ALPHA recruited adult patients (aged ≥ 18 years) with PNH and csEVH (Hb ≤ 9.5 g/dL, absolute reticulocyte count ≥ 120 × 109/L) who received stable doses of ravulizumab or eculizumab for ≥ 6 months before enrollment. BTH was determined by the investigator (no per-protocol definition was applied). PEGASUS recruited adult patients with PNH and Hb &lt; 10.5 g/dL who received stable doses of eculizumab for ≥ 3 months before enrollment. BTH was defined as ≥ 1 new or worsening symptom or sign of intravascular hemolysis with LDH ≥ 2 × the upper limit of normal (ULN) after a reduction of &lt; 1.5 × ULN during treatment. Results For up to 2.5 years of add-on danicopan therapy, 5/84 patients (6.0%) experienced ≥ 1 BTH event (7 events in total), equating to an exposure-adjusted BTH rate of 6.0 per 100 patient-years (PY). Of these events, 6/7 (85.7%) were reported to be either mild (n = 3) or moderate (n = 3) and were associated with Hb levels of 7.4-9.2 g/dL; LDH level was ≤ 2.0 × ULN in 5 events and 2.2 × ULN in 1 event. One event was considered severe and was associated with Hb of 7.3 g/dL and LDH ≤ 2.0 × ULN. All BTH events reported during add-on danicopan therapy were resolved without transfusion, dose modification or treatment withdrawal. During the first 48 weeks of pegcetacoplan treatment, 19/80 patients (23.8%) experienced ≥ 1 BTH event (26 events in total), equating to an exposure-adjusted BTH rate of 33.5 per 100 PY. Events were either moderate (n = 14) or severe (n = 12) and were associated with increased LDH levels of up to 18.3 × ULN. Hb levels were reduced, with 5 events reporting Hb &lt; 6.5 g/dL. Of the 19 patients who experienced BTH, 11 (57.8%) required transfusions, 4 (21.1%) required rescue treatment with eculizumab and 8 (42.1%) discontinued treatment. For up to 3.0 years, 4 additional patients experienced ≥ 1 BTH event (clinical data unavailable). Conclusions BTH events can increase the risk of severe, potentially life-threatening complications with PNH and therefore must be minimized when possible. Evidence suggests that proximal inhibitor monotherapies can be associated with severe BTH events (Notaro et al. N Engl J Med 2022). These events have been managed by higher than label pegcetacoplan dosing (including switching to intravenous administration), C5i rescue and/or transfusions (Griffin et al. Am J Hematol 2024). Add-on danicopan therapy to background ravulizumab or eculizumab in patients with PNH and csEVH resulted in a low rate of BTH events, which were mostly mild to moderate and managed without transfusions or dosing regimen changes. Dual inhibition of C5 and factor D is a viable treatment option for this at-risk population.
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Kudlay, D. A., B. A. Bakirov, and V. N. Pavlov. "Biotechnological products for the treatment of complement system disorders including paroxysmal nocturnal hemoglobinuria: currently available and in development." Pediatric Hematology/Oncology and Immunopathology 19, no. 3 (2020): 164–72. http://dx.doi.org/10.24287/1726-1708-2020-19-3-164-172.
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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal blood disorder caused by somatic mutations in phosphatidylinositol glycan, class A gene (PIG-A) in hematopoietic stem cells which manifests as haemolytic anemia, bone marrow failure, thromboses, impaired renal function, and other severe clinical symptoms. The management of PNH is a clinical challenge requiring a comprehensive approach. Over the past decade, target therapy with eculizumab, an antibody inhibitor of terminal complement activation, has played a key role in the treatment of PNH. Eculizumab is the first humanized anti-C5 monoclonal antibody that was proven effective in inhibiting the complement system and was approved as a standard treatment for PNH in many countries. Elizaria, the first biosimilar version of eculizumab, whose similarity to the original drug in terms of efficacy and safety was demonstrated in clinical trials, has been widely used in Russia since 2019. New complement inhibitors classified by their mechanism of action into inhibitors targeting complement component C5 (the terminal pathway) and those targeting early phases of complement activation cascade (the proximal pathway) are currently in development. These new drugs include monoclonal antibodies, small molecules, small peptide inhibitors, small interfering RNA, and recombinant proteins based on endogenous regulators of complement activation.
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Villegas, Ana, Ataulfo Gonzalez, Fatima Matute, Jorge Martinez Nieto, and Felix de la Fuente. "Value Of Magnetic Resonance Imaging In The Study and Follow-Up Of Paroxysmal Nocturnal Hemoglobinuria." Blood 122, no. 21 (2013): 4872. http://dx.doi.org/10.1182/blood.v122.21.4872.4872.
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Abstract Introduction Renal damage is relatively frequent in Paroxysmal Nocturnal Hemoglobinuria (PNH). Iron accumulation from hemolysis in the renal tubules has been found to be one of the triggering factors. Hemosiderin accumulates in the epithelial cells of the proximal renal tubules localized in the renal cortex, and they can be measured (and monitoring) using magnetic resonance imaging (MRI). Methods We studied 7 PNH patients with MR using T2-weighted gradient echo and multiecho sequences. We quantified renal, hepatic and myocardial iron with T2* relaxometry model. Four of these patients were studied at diagnosis and after 1 year of treatment with eculizumab. In 2 of them the MRI was done after 2 and 3 years respectively of treatment with eculizumab. One patient was studied after 8 months on eculizumab, and MRI was repeated at 12 and 24 months. Liver and myocardial iron deposition was quantified in all cases. Results At diagnosis the median hemoglobin of the 7 patients was 8.9 g/dl (8.2-12-4), the PNH median PNH clone size was 77% (60-90) and the median LDH level was 2340 U/L (1100-3600). Three patients presented an important accumulation of iron in the renal cortex, with much lower signal intensity than the medulla in the T2-weighted MR images. One patient with mild hemolysis (Hb 12.4 g/dl, 20% reticulocytes and 1,100 LDH) did not present iron accumulation in the renal cortex, and neither did the 2 patients studied after 2 a 3 years of eculizumab treatment. All the patients improved, presenting median of Hb of 11,2 g/dl ( 9,5-12,9) and of LDH of 520 U/L ( 430- 721). The patient studied after 8 months showed an increase of iron in the renal cortex that persisted, despite the improvement with the treatment with eculizumab, with increase of the Hb and decrease of the LDH levels; this patients had a C hepatitis and positivity on the hemochromatosis genes C282Y/H63D, with important iron hepatic overload (11-17 mgFe/g). In the rest of the patients the hepatic iron was normal, with values from 0.5 to 2 mgFe/g, except in one case where the levels were higher (10 mgFe/g) due to previous transfusions used to treat an aplastic anemia pre-PNH. Myocardial iron was normal in the 7 patients, with values ranging from 33 to 60 ms in T2. Only one of the patients presented several episodes of acute renal insufficiency, related with hemolytic crisis, with residual proteinuria, that disappeared when treated with eculizumab. Conclusions A diffuse signal loss in the renal cortex without liver and spleen alteration is indicative of intravascular hemolysis, suggesting PNH. Serial MRI studies of iron overload in the renal cortex can be used for the diagnosis, and for monitoring the effects of treatment. Disclosures: No relevant conflicts of interest to declare.
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Veeramreddy, Padmaja, and Srinivasa Reddy Sanikommu. "Efficacy and Safety of Single Agent Proximal Complement Inhibitors in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients with Residual Anemia Despite of Adequate Terminal Complement Inhibitor Use." Blood 142, Supplement 1 (2023): 5650. http://dx.doi.org/10.1182/blood-2023-190291.
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Background: Introduction of C5 inhibitors is a major advancement in the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) patients. First Eculizumab and then Ravulizumab significantly improved anemia by controlling intravascular hemolysis (IVH), reduced thrombosis risk, improved quality of life and prolonged survival. However, a significant proportion of PNH patients remain anemic with transfusion dependence despite maximal C5 inhibition due to C3 mediated residual extravascular hemolysis (EVH). Recently two randomized, open label, controlled trials with proximal complement inhibitors were studied in this patient population comparing against C5 inhibitors as single agents with excellent results. Here we compare efficacy and safety data of proximal complement inhibitors pegcetacoplan (C3 inhibitor), Iptacopan (factor b inhibitor) based on published or presented data. Methods: We compared the efficacy and safety data of randomized portion of PEGASUS and APPLY-PNH trials. PEGASUS trial is a phase 3, randomized, open label, active-comparator controlled trial with Pegcetacoplan (a pegylated pentadecapeptide that targets C3) compared efficacy and safety against eculizumab in PNH patients with Hb &lt;10.5 despite of treatment with Eculizumab (Hillerman, et al NEJM 2021;384). Primary end point of the study was mean change in Hb level from baseline to week 16. APPLY-PNH is an open label randomized, multicenter phase 3 trial compared Iptacopan 200 mg BID (oral factor b inhibitor) monotherapy with standard of care C5 inhibition therapy. (Regis P. de Latour et al. Blood (2022) 140 (Suppl 2): LBA-2). Primary end points of the trial were Hematological response defined as an increase in Hb of ≥ 2 g/dL from baseline and Hb ≥ 12 g/dL in absence of transfusions. Secondary end points included number of clinical and hematological markers of hemolysis and safety. Results: Summarized in table 1. PEGASUS trial included 80 patients with 41 in pegcetacoplan arm and 39 in Eculizumab arm. APPLY-PNH included 97 patients with 62 in Iptacopan arm compared to 35 in standard of care anti C5 therapy. Majority of baseline characteristics were similar between two studies. Mean age in both studies was around 50 years and close to 2/3rd of patients in each study were females. Median duration of prior C5 therapy was between 3-4 years in both studies. More than half of patients in both studies required PRBC transfusions in preceding months prior to enrollment. Baseline mean Hb was between 8-9 g/dL, LDH between 250-300 U/L, mean absolute retic count (ARC) 190-200x109/L. Both studies showed superiority in change from baseline Hb with +2.69 g/dL in PEGASUS trial with all available data regardless of transfusion events and +3.63 in APPLY-PNH trial. Both studies showed either noninferiority or superiority in freedom from transfusions and change in ARC. Interestingly, LDH change was not significant in both studies. Change from baseline fatigue FACIT-score was numerically better but not tested in PEGASUS trial and was superior in APPLY-PNH. No major vascular events or serious infections by encapsulated bacteria were reported in either study. Breakthrough hemolysis was reported in 4 out of 40 patients in PEGASUS trial that led to treatment discontinuation in 3 patients and 2 out of 62 patients in APPLY-PNH trial, however none of them required treatment discontinuation. Conclusions: PEGASUS and APPLY-PNH trials showed that in patients with persistent anemia despite C5 inhibitor therapy, proximal complement inhibition with either pegcetacoplan (C3 inhibitor) or Iptacopan (factor b inhibitor) as a single agent showed significant improvement in Hemoglobin with higher rate of transfusion independence with control of extra vascular hemolysis while maintaining intravascular hemolysis control with no serious infections. These studies represent another major advancement in the management of PNH patients. Long term follow up is needed regarding safety and to identify better ways to manage breakthrough hemolysis in patients on proximal complement inhibitors.
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Vara, Míriam, Maite Moreno, Javier Arzuaga, Sara Hormaza, and Juan Carlos García-Ruiz. "A Case Report of a Patient with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan Who Underwent Major Surgery." Blood 142, Supplement 1 (2023): 5656. http://dx.doi.org/10.1182/blood-2023-182242.
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Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterized by intravascular hemolysis, thrombosis and bone marrow failure. The appearance of the anti-C5 monoclonal antibody eculizumab revolutionized the treatment of PNH, controlling hemolysis and the incidence of thrombosis. However, some patients persist with anemia, due in part to extravascular C3-mediated hemolysis. More recently, the anti-C3 monoclonal antibody pegcetacoplan, which blocks the most proximal part of the complement cascade, has been marketed in Europe, achieving improvements in anemia in these patients. However, intercurrent infectious episodes or surgical interventions can trigger a hemolytic flare, so dose adjustments are necessary to prevent their occurrence. There is hardly any published information or established consensus on how to treat these patients. We present this case as an example of a successful treatment of a patient diagnosed with PNH under treatment with pegcetacoplan who has undergone major surgery. A 67 year-old man was diagnosed with aplastic anemia in 1997 and treated with immunosuppression (cyclosporine and oxytosone). In 2000, he presented his first intravascular hemolytic crisis with HPN clone detection. He presented several intravascular hemolytic crises for which he was treated with erythropoiesis-stimulating agents, corticosteroids and transfusions. In 2010, due to deterioration of renal function because of acute hemolysis episode, he started treatment with eculizumab. A reduction in the number of hemolytic crises was observed. However, he required an increase in the dose and frequency of administration of eculizumab due to pharmacokinetic breakthrough hemolysis. After one month of treatment, a positive direct coombs test appeared and presented anemia due to extravascular hemolysis, for which he again required treatment with corticosteroids on specific occasions. For this reason, in December 2022, he started treatment with pegcetacoplan at the usual dose of 1080 mg twice a week subcutaneously (sc). Prior to the start of pegcetacoplan, the patient had hemoglobin levels of 10.3 g/dL, hyperbilirubinemia of 3.2 mg/dL (indirect 2.6 mg/dL), consumed haptoglobin, elevated lactate dehydrogenase (LDH) of 281 U/L and reticulocytosis of 5-6%. Subsequently, since the beginning of pegcetacoplan, he presented clinical improvement, stable hemoglobin (12-13 g/dL) and normalization of reticulocytes, LDH and bilirubin levels. The haptoglobin has remained low until the present time. In June 2023, the patient underwent major surgery consisting of radical prostatectomy due to a benign prostatic hypertrophy. Suspecting that it might provoke a hemolytic crisis due to surgical stress, the dose of pegcetacoplan was increased as recommended by clinical experts to a dose of 1080 mg every 72 hours sc from one week prior to surgery until one week after. The procedure was carried out without incident and without an increase in hemolysis parameters. This is the first case report of a patient with PNH treated with pegcetacoplan undergoing major surgery in Spain. In this patient, the perioperative dose increase was successful in preventing the development of a hemolytic crisis.
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Jang, Jun-Ho, Lily LL Wong, Bor-Sheng Ko, et al. "12-Month Analysis of a Phase 2 Study of Iptacopan (LNP023) Monotherapy for Paroxysmal Nocturnal Hemoglobinuria." Blood 138, Supplement 1 (2021): 2173. http://dx.doi.org/10.1182/blood-2021-152518.
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Abstract Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematological disorder caused by somatic mutations in the phosphatidylinositol glycan A (PIGA) gene in hematopoietic stem cells, resulting in complement alternative pathway (AP)-mediated severe hemolysis, life-threatening thrombosis, and impaired bone marrow function. The current standard-of-care for PNH consists of anti-C5 blockade with either eculizumab or ravulizumab. While both monoclonal antibodies effectively control intravascular hemolysis (IVH), reduce thrombosis and improve long-term survival, a significant proportion of patients remains anemic and continues to require transfusions, largely due to persistent extravascular hemolysis (EVH). Conversely, pegcetacoplan, a recently FDA-approved anti-C3 inhibitor, prevents both IVH and EVH and showed superiority to eculizumab in improving hemoglobin (Hb) levels in PNH. Nevertheless, the need for effective oral treatment options in PNH remains unmet. Iptacopan (LNP023) is a new, oral, selective and potent first-in-class inhibitor of factor B, a key component of the AP. Recent phase 2 data showed that iptacopan effectively controls both IVH and EVH and leads to rapid, transfusion-free improvements in Hb levels in the majority of PNH patients. Methods: CLNP023X2204 (NCT03896152) is a multicenter, randomized, open-label phase 2 study in adult PNH patients with active hemolysis and no complement inhibitor treatment within 3 months prior to study entry. Patients are randomized to receive twice daily (BID) iptacopan in one of two dose-sequences, either 25 mg for 4 weeks followed by 100 mg for up to 2 years (Cohort 1) or 50 mg followed by 200 mg (Cohort 2). The key objectives are to assess the effect of iptacopan on markers of IVH/EVH (incl. lactate dehydrogenase (LDH)) and on Hb levels, as well as safety. 12-month interim results are summarized below. Results: The study has completed enrolment. A total of 13 patients (mean age 38.2 years, 7 female) were randomized to either Cohort 1 (n=7) or 2 (n=6). Mean (SD) lab values at baseline were LDH 2097.8 (911.2) U/L, reticulocytes 203.3 (82.9) x10E9/L, bilirubin 32.4 (10.1) µmol/L, and Hb 85.8 (13.2) g/L, and most patients required red blood cell transfusions in the prior 12 months (median 3.0, range 0-19). At the time of the interim analysis, 11 patients had been treated with iptacopan for at least 52 weeks, with a maximum treatment duration of 81 weeks; 2 patients discontinued treatment early, one after 2 days due to a non-serious adverse event of headache (hence not evaluable for the primary endpoint), the other after 13 weeks due to physician decision. Amongst the 12 evaluable patients, all of whom were anti-C5 naive, all reached the primary endpoint of lowering LDH by at least 60% within the first 12 weeks. The LDH response was rapid and durable, with all patients treated with ≥50 mg BID reaching this threshold after only one week of treatment and all ongoing patients except one maintaining the threshold up until the data cutoff, i.e., for at least 52 weeks. Equivalent improvements were also observed for other markers of IVH and EVH. Similarly, Hb levels improved significantly and durably in most patients, and all except one of the ongoing patients have remained transfusion-free since the start of iptacopan treatment. Moreover, no thromboembolic events occurred during the study, and the FACIT fatigue score improved significantly in most patients. Iptacopan monotherapy was safe, with no severe or serious adverse reported up to the data cutoff. Conclusion: Iptacopan is a new, well tolerated oral complement AP inhibitor that blocks both IVH and EVH in adult PNH patients with hemolytic PNH. 12-month results from this non-pivotal study demonstrate that iptacopan monotherapy leads to rapid and durable improvements in various hemolytic markers and meaningful and sustained clinical benefit as seen in improvements in Hb levels, transfusion requirement and FACIT fatigue score. These results suggest that proximal inhibition of the complement cascade parallels and further improves the hematological benefit seen with anti-C5 therapies, paving the way for the phase 3 evaluation of iptacopan as potentially new oral first-line therapy for patients with PNH. Figure 1 Figure 1. Disclosures Wong: Astellas Pharma, INc.: Research Funding. Li: Novartis: Current Employment, Current equity holder in publicly-traded company. Rozenberg: Novartis: Current Employment, Current equity holder in publicly-traded company. Nidamarthy: Novartis: Current Employment, Current equity holder in publicly-traded company. Chawla: Novartis: Current Employment, Current equity holder in publicly-traded company. Junge: Novartis: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Iptacopan (LNP023) is a new, oral, selective and potent first-in-class inhibitor of factor B, a key component of the complement alternative pathway. It is currently being investigated in paroxysmal nocturnal hemoglobinuria (PNH) as well as in several renal indications.
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Peffault De Latour, Regis, Carlos M. de Castro, Jeffrey Szer, et al. "Pegcetacoplan Is Superior to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Regardless of Prior Transfusion Requirement." Blood 136, Supplement 1 (2020): 32–33. http://dx.doi.org/10.1182/blood-2020-141061.
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INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by chronic complement-mediated intravascular and extravascular hemolysis. In the phase 3 PEGASUS study (NCT03500549), pegcetacoplan, a C3 inhibitor targeting the proximal complement pathway, was superior to eculizumab (ECU) on the primary endpoint of hemoglobin (Hb) change from baseline at week 16, and improved clinical and hematologic parameters. Additional analyses assessed if any groups of patients might experience further benefit from pegcetacoplan. METHODS Patients ≥18 years old with a diagnosis of PNH and persistent anemia (Hb &lt;10.5 g/dL) at baseline, despite treatment with stable doses of ECU for ≥3 months, entered a 4-week run-in period during which all patients continued their current dose of ECU with the addition of twice-weekly pegcetacoplan (1080 mg, self-administered subcutaneously). On study day 1, patients were stratified based on baseline platelet count and prior transfusion requirements, and randomized 1:1 to monotherapy with pegcetacoplan or ECU for 16 weeks. The primary endpoint of change from baseline (before first dose of pegcetacoplan) at week 16 in Hb and key secondary endpoints (change from baseline at week 16 in absolute reticulocyte count [ARC] and lactate dehydrogenase [LDH]) were analyzed using a mixed-effect model for repeated measures by subgroups based on baseline age group, sex, race, number of packed red blood cell transfusions (&lt;4 vs ≥4) within the 12 months prior to day −28, and platelet count at screening (&lt;100,000/mm3 vs ≥100,000/mm3). The key secondary endpoint of transfusion avoidance was analyzed by calculating the number and proportion of patients who were transfusion-free and also analyzed by subgroups. For patients transfused during the randomized control period or who withdrew from the study, the primary and secondary data endpoints up to the transfusion or time of withdrawal were included, but all subsequent values were censored. RESULTS Pegcetacoplan treatment was associated with significantly greater increases in Hb levels than ECU at week 16, regardless of baseline age group, sex, race, prior transfusions, or platelet count (Tables 1-2). At week 16, regardless of baseline platelet count strata, mean Hb significantly increased from baseline in the pegcetacoplan group and decreased in the ECU group. The proportion of transfusion-free patients was similar in the pegcetacoplan group, regardless of age (≤65 years, 87.1%; &gt;65 years, 80%), sex (female, 81.5%; male, 92.9%), race (Asian, 100%; black, 100%; white, 75.0%), transfusion strata (&lt;4 transfusions, 85.0%; ≥4 transfusions, 85.7%), or platelet strata (&lt;100,000/mm3, 83.3%; ≥100,000/mm3, 86.2%). A smaller proportion of patients were transfusion-free with ECU, regardless of age (≤65 years, 18.8%; &gt;65 years, 0%), sex (female, 18.2%; male, 11.8%), race (Asian, 28.6%; black, 0%; white, 16.0%), transfusion strata (&lt;4 transfusions, 31.3%; ≥4 transfusions, 4.3%), or platelet strata (&lt;100,000/mm3, 0%; ≥100,000/mm3, 20.0%). Similar trends for more favorable results with pegcetacoplan versus ECU were seen across the prespecified subgroups for ARC and LDH. CONCLUSIONS In this prespecified stratified analysis of the phase 3 PEGASUS study of patients with PNH and persistent anemia, mean Hb levels increased significantly more, the proportion of transfusion-free patients was significantly higher, ARC change from baseline at week 16 was significantly lower, and LDH decreases were larger with pegcetacoplan versus ECU, regardless of baseline age group, sex, race, prior transfusion numbers, and platelet count. Disclosures Peffault De Latour: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion: Honoraria, Research Funding; Apellis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Other: Steering committee; Biocryst: Honoraria, Other: Data monitoring committee. Szer:Apellis: Consultancy; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usuki:Alexion: Research Funding, Speakers Bureau; Apellis: Research Funding; Chugai: Research Funding; Novartis: Research Funding, Speakers Bureau. Hillmen:Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees. Hamdani:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.
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Gandhi, Shreyans, Regis Peffault De Latour, Katharina Pannagl, et al. "Incremental Effectiveness of Iptacopan Compared with C5 Inhibitors in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from a Modelling Analysis." Blood 144, Supplement 1 (2024): 5012. https://doi.org/10.1182/blood-2024-201424.
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Objective Intravenous infusion complement-5 inhibitors (C5i; eculizumab, ravulizumab) have been the primary therapies for patients with paroxysmal nocturnal hemoglobinuria (PNH). New treatments with different mechanisms of action have been approved recently, including iptacopan, a Factor B proximal complement inhibitor that is the first oral monotherapy for the treatment of adult patients with PNH. Health technology assessments (HTA) are regularly conducted to inform decision making regarding the funding or reimbursement of new drugs and often include cost-effectiveness analyses, which compare costs and outcomes (such as effectiveness) of different interventions based on an economic model. Outcomes are expressed in quality-adjusted life years (QALYs) which capture both the quality, and length of life with each intervention. The objective of this analysis was to estimate the incremental effectiveness of iptacopan compared to C5i for the treatment of adult patients with PNH over a lifetime horizon. Methods A semi-Markov cost-effectiveness model was developed with four mutually exclusive health states: ‘No Transfusion and No Anemia’; ‘No Transfusion and Anemia’ (defined as hemoglobin &lt;10 g/dL); ‘Transfusion’; and ‘Death’. Data from two Phase 3 studies of iptacopan were used: APPLY-PNH (NCT04558918) in C5i-experienced patients with persistent anemia (iptacopan vs. C5i) and APPOINT-PNH (NCT04820530) in C5i-naïve patients (single-arm iptacopan trial). Data from a real-world cohort of C5i-treated patients in France and UK (APPEX study; NCT05842486) was also used. Using individual patient-level data from these studies, a regression model was developed to predict the probability of patients transitioning between health states in 4-weekly intervals for each treatment. Quality of life in each health state was incorporated as treatment-specific utility values based on EQ-5D data from APPOINT-PNH and APPLY-PNH. QALYs were calculated by multiplying the proportion of patients in each health state over time by the number of years spent in the respective health state, and the corresponding utility value, and discounted at 3.5% annually. Here we report the overall QALYs associated with each treatment and the difference between them (incremental QALYs) for the C5i-naïve and C5i-experienced populations separately, considered over a lifetime horizon. Results In the C5i-naïve population, at 10 years, a higher proportion of patients treated with iptacopan (95%) were in the ‘No Transfusion and No Anemia’ health state compared to C5i (40%). Less than 1% of patients treated with iptacopan were in the ‘Transfusion’ state compared to 16% of patients treated with C5i. Over a lifetime horizon, this resulted in total QALYs of 17.37 with iptacopan and 14.95 with C5i, with incremental QALYs of 2.42 in favour of iptacopan. Similarly, in the C5i-experienced population with persistent anemia, at 10 years, a higher proportion of patients treated with iptacopan (87%) were in the ‘No Transfusion and No Anemia’ health state compared to C5i (11%). Less than 1% of patients treated with iptacopan were in the ‘Transfusion’ state compared to 41% of patients treated with C5i. Over a lifetime horizon, this resulted in total QALYs of 15.20 with iptacopan and 12.67 with C5i, with incremental QALY of 2.53 in favour of iptacopan. Conclusion In this modelling analysis, iptacopan demonstrated improved effectiveness in terms of more patients achieving freedom from transfusions and anemia, and more QALYs gained, compared to C5i in both C5i-naïve and -experienced patients with PNH. To determine the cost-effectiveness of iptacopan compared to C5i, further consideration of all costs associated with these treatments is required in country-specific analyses aligned with local HTA requirements.
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Snellman, Josefin, Ranjan Tiwari, Abdulfaheem Khan, Sviatlana Rizk, and Virginia Pilipovic. "Iptacopan Treatment Improves Clinical Parameters in a Real-World Cohort with Paroxysmal Nocturnal Hemoglobinuria: Evidence from a Managed Access Program." Blood 144, Supplement 1 (2024): 5692. https://doi.org/10.1182/blood-2024-209893.
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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.
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Risitano, Antonio, Ilene C. Weitz, Carlos M. de Castro, et al. "Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)." Blood 136, Supplement 1 (2020): 44–45. http://dx.doi.org/10.1182/blood-2020-142166.
Full textAbstract:
INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, nonmalignant hematologic disease characterized by complement-mediated red blood cell hemolysis. The current standard of care for patients with PNH is C5 inhibition. Anemia persists in up to ~70% of patients receiving eculizumab and is attributed to persistent intravascular hemolysis (IVH) and mostly to C3-mediated extravascular hemolysis (EVH). Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both IVH and EVH. PEGASUS is a phase 3, open-label, active-comparator controlled study of efficacy and safety of pegcetacoplan versus eculizumab. This post hoc analysis of data from PEGASUS categorized the clinical response to pegcetacoplan or ECU in patients with PNH and hemoglobin &lt;10.5 g/dL (despite stable ECU for ≥3 months). METHODS Hematologic response to treatment was categorized (per Risitano AM, et al. Front Immunol. 2019;10:1157) as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count (ARC). Complete response: no transfusions required, stable hemoglobin in the normal range, and no evidence of hemolysis (ie, LDH ≤1.5× upper limit of normal, ARC ≤150,000/µL). Major response: no transfusion, normal hemoglobin, but with evidence of hemolysis (LDH &gt;1.5× upper limit of normal and/or ARC &gt;150,000/µL). Good response: no transfusion, but with chronic mild anemia or evidence of hemolysis. Partial response: chronic moderate anemia and/or occasional transfusions (&lt;3 units/6 months). Minor response: regular transfusions required (3-6 units/6 months). No response: regular and frequent transfusions required (&gt;6 units/6 months). Nine patients (6 from the pegcetacoplan arm and 3 from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16. Although these 9 patients were manually categorized identically by the lead and senior author in a blinded, independent manner, they were not included among these data. RESULTS The intention-to-treat population was comprised of 41 patients randomized to pegcetacoplan and 39 patients randomized to eculizumab. Four patients in the pegcetacoplan arm and 1 patient in the eculizumab arm were not evaluable for analysis due to incomplete data at week 16. Altogether, 61.0% of patients (25/41) in the pegcetacoplan arm have achieved at least a good hematological response, in contrast to 5.1% (2/39) of the eculizumab arm. At week 16, the distribution of response categories was as follows (Figure): in the pegcetacoplan arm and eculizumab arm, respectively, complete responses were 36.6% and 0%, good responses were 24.4% and 5.1%, partial responses were 12.2% and 33.3%, minor responses were 2.4% and 23.1%, and no responses were 0% and 28.2%. The addition of the 9 manually categorized patients did not significantly alter the proportions reported here. Among the factors that may contribute to heterogeneity of hematologic response to treatment are impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure was ruled out, and no difference in LDH was observed, suggesting that the major factor accounting for the difference between the 2 arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells). CONCLUSION In PEGASUS, treatment with pegcetacoplan resulted in a greater proportion of patients with better hematological responses compared to eculizumab. These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematological improvement in the treatment of PNH. Disclosures Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. de Castro:Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Biocryst: Honoraria, Other: Data monitoring committee; Apellis: Consultancy, Honoraria, Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.
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Brodsky, Robert A., Regis Peffault De Latour, Scott T. Rottinghaus, et al. "A Prospective Analysis of Breakthrough Hemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria." Blood 132, Supplement 1 (2018): 2330. http://dx.doi.org/10.1182/blood-2018-99-110874.
Full textAbstract:
Abstract Background/Objective: Breakthrough hemolysis (BTH) is the return of hemolytic disease activity during treatment with complement C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH). BTH may be associated with inadequate C5 inhibition or complement activating conditions (eg, infection). Despite reports that up to 19% of patients (pts) receiving eculizumab may experience BTH, there is no commonly accepted definition of BTH. The definition of BTH was derived from literature review and expert consensus. BTH was defined as ≥1 new or worsening symptom/sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of lactate dehydrogenase (LDH) ≥2 times the upper limit of normal (ULN). In the 2 largest pivotal studies in PNH pts to date, ravulizumab q8w was statistically significantly noninferior to eculizumab 900 mg q2w, with point estimates favoring ravulizumab for all primary (LDH normalization, transfusion avoidance [study 301], percent change in LDH [study 302]) and key secondary endpoints (including BTH). Ravulizumab reduced free C5 levels to <0.5 μg/mL in all pts at all times; eculizumab did not consistently achieve this level of complement inhibition, providing a mechanistic basis for consistency of the point estimates for all endpoints. In study 301, LDH levels had to be decreased to <1.5 xULN prior to a BTH episode. Here we report BTH prevalence and causality using a common definition in the setting of 2 well-controlled clinical studies. Methods: Two phase 3, randomized, open-label, noninferiority, multicenter studies (study 301, NCT02946463; study 302, NCT03056040) included pts ≥18 years of age with confirmed PNH diagnoses. Pts in study 301 were naive to C5 inhibitor therapy, with LDH ≥1.5 xULN and ≥1 sign/symptom of PNH at screening. Pts in study 302 were stable on eculizumab treatment for ≥6 months, with LDH ≤1.5 xULN at screening. Pts received weight-based dosing of ravulizumab q8w or the approved eculizumab dose (900 mg q2w) for 183 days. Higher eculizumab doses were prohibited. Results: In study 301, 246 pts received ravulizumab (n=125) or eculizumab (n=121); in study 302, 195 pts received ravulizumab (n=97) or eculizumab (n=98). Ravulizumab was associated with fewer episodes of BTH than eculizumab in both studies. In study 301, 5 pts (4.0%) experienced BTH in the ravulizumab group vs 13 pts (10.7%) in the eculizumab group; between-group difference (95% confidence interval [CI]) was −6.7% (−14.21%, 0.18%; P=0.0558 for superiority). In the eculizumab group, 7/15 events were temporally associated with elevations in free C5 (C5 ≥0.5 μg/mL), suggesting inadequate C5 inhibition. No BTH events in the ravulizumab group were associated with inadequate C5 inhibition. Among the BTH events in the ravulizumab group, the majority, 4/5 events, were associated with infection. In the eculizumab group, infection was associated with 6/15 BTH events, including 2 infections in pts with inadequate C5 inhibition. In study 302, no pts in the ravulizumab group experienced BTH vs 5 pts (5.1%) in the eculizumab group (1 pt had 3 BTH events, requiring hospitalization and study discontinuation for lack of efficacy); the between-group difference (95% CI) was −5.1% (−18.99%, 8.89%). Four of 7 BTH events in the eculizumab group were associated with concomitant elevations in free C5. Infection was associated with 3/7 BTH events, including 1 infection in a pt with inadequate C5 inhibition (Table). There was no clear pattern for timing of BTH events. All BTH episodes in the eculizumab groups were reported at the q2w study visits associated with pharmacokinetic (PK) troughs. All BTH episodes in the ravulizumab groups were reported at the q2w study visits, but not necessarily at q8w PK troughs. Conclusions: No BTH events in the ravulizumab group were associated with elevations in free C5. In contrast, pts treated with eculizumab 900 mg q2w experienced multiple BTH events with elevations in free C5 suggesting suboptimal C5 control. Similar numbers of pts receiving ravulizumab or eculizumab experienced infection-related BTH, possibly due to proximal complement activation. Differences in BTH rates for ravulizumab vs eculizumab may be due to improved pharmacodynamics (C5 inhibition throughout the dosing interval) and the optimized ravulizumab dosing regimen. Figure. Figure. Disclosures Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Röth:Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bioverativ: Consultancy, Honoraria. Risitano:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Hillmen:Novartis: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Volles:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Damokosh:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Ortiz:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Shafner:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hill:Bioverativ: Consultancy, Honoraria; Akari: Consultancy, Honoraria; Ra Pharma: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Schrezenmeier:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding.
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Hill, Anita, Caroline I. Piatek, Régis Peffault de Latour, et al. "Breakthrough Hemolysis in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Ravulizumab: Results of a 52-Week Extension from Two Phase 3 Studies." Blood 134, Supplement_1 (2019): 952. http://dx.doi.org/10.1182/blood-2019-128929.
Full textAbstract:
INTRODUCTION In patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) receiving eculizumab, approximately 11%-27% may experience breakthrough hemolysis (BTH)-the return of hemolytic disease activity. BTH may be associated with inadequate C5 inhibition or complement-activating conditions (CACs; eg, infection). Although there is no broad consensus regarding the definition of BTH, this study defined BTH based on literature review and expert consensus: ≥1 new or worsening sign or symptom of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin &lt;10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated lactate dehydrogenase (LDH) (≥2 × ULN) after prior LDH reduction to &lt;1.5 × ULN on therapy. Ravulizumab, an innovative long-acting C5 complement inhibitor, was recently approved in the United States, Japan, and Europe for the treatment of PNH. In two phase 3 trials, ALXN1210-PNH-301 (301; NCT02946463) and ALXN1210-PNH-302 (302; NCT03056040), ravulizumab (q8w) was shown to be noninferior to eculizumab 900 mg (q2w) for all primary and key secondary endpoints (including BTH). Each study had a 26-wk randomized primary evaluation period, followed by an extension period during which pts could receive ravulizumab for up to 2 y. In the current analysis, pt-level data were evaluated to assess causes and clinical parameters associated with BTH incidences reported up to 1 y in the two phase 3 trials. METHODS The trials were phase 3, randomized, open-label, noninferiority, multicenter studies. Eligible pts were ≥18 y with confirmed PNH diagnosis. Pts in study 301 were naive to C5 inhibitor therapy, with LDH of ≥1.5 × ULN and ≥1 sign/symptom of PNH at screening. Pts in study 302 were stable receiving eculizumab treatment for ≥6 mo, with LDH of ≤1.5 × ULN at screening. Pts received weight-based dosing of ravulizumab q8w or the approved eculizumab dose (900 mg q2w) for 183 d; in the extension, eligible pts continued (R-R arm) or switched to ravulizumab (E-R arm). The outcome of interest was the proportion of pts with BTH during the extensions of 301 and 302 (wks 27-52), causes, and clinical parameters associated with BTH incidents. BTH causation was determined by clinical review and categorized as related to inadequate C5 inhibition (free C5 ≥0.5 μg/mL), CAC due to an inciting event (eg, infection, trauma, surgery), or unrelated to either event. RESULTS Study 301: 243 pts entered the extension period (R-R arm: n=124; E-R arm: n=119). In both groups, 99% of pts who had no BTH during wks 0-26 experienced no BTH incidents during wks 27-52. Four pts in the R-R arm experienced BTH during wks 27-52, of which 3 pts had experienced BTH during wks 0-26. In the E-R arm, there were fewer BTH events during wks 27-52 compared with wks 0-26 (Table A). Two pts experienced BTH after switching to ravulizumab in the E-R arm, of which 1 had experienced BTH during wks 0-26. During wks 27-52, 2 BTH events (1 in each arm) were associated with infection and 4 BTH events in the R-R arm and 1 in the E-R arm were unrelated to free C5 elevation or reported infection. Study 302: 191 pts entered the extension period (R-R arm: n=96; E-R arm: n=95). Of these pts, 97% in the R-R arm and 100% in the E-R arm who had no BTH during wks 0-26 had no BTH incidents during wks 27-52. Three pts in the R-R arm experienced BTH during wks 27-52. In the E-R arm, there were fewer BTH events during wks 27-52 compared with wks 0-26 (Table B). One pt experienced BTH after switching to ravulizumab; this pt previously experienced BTH during wks 0-26. During wks 27-52, 2 BTH events in the R-R arm and 1 event in the E-R arm were associated with infection, and 1 BTH event in the R-R arm was unrelated to free C5 elevation or reported infection. In both studies, no BTH incidents were associated with free C5 of &gt;0.5 μg/mL (the threshold associated with complete inhibition of C5) during wks 27-52 while on ravulizumab treatment. CONCLUSIONS During wks 27-52, in both studies, the number of pts who experienced BTH events was similar to that in wks 0-26 in the R-R group, and fewer pts experienced BTH events after switching from eculizumab to ravulizumab. No BTH events were associated with elevations in free C5 to &gt;0.5 μg/mL in pts taking ravulizumab. Similar numbers of pts initially receiving ravulizumab or eculizumab experienced infection-related BTH events, possibly due to proximal complement activation. Disclosures Hill: Bioverativ: Honoraria; Alexion: Honoraria; Regeneron: Honoraria; Novartis: Honoraria; Roche: Honoraria; Apellis: Honoraria; Akari: Honoraria; Ra Pharma: Honoraria. Piatek:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Wells:Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Pavani:Alexion: Employment. Liu:Alexion: Employment. Ortiz:Alexion: Employment. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kulasekararaj:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Risitano, Antonio M., Regis Peffault De Latour, Jun Ho Jang, et al. "Exposure-Response Relationships between the Complement Factor B Inhibitor Iptacopan and Lactate Dehydrogenase (LDH) and Hemoglobin (Hb) in Patients (Pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH)." Blood 142, Supplement 1 (2023): 5643. http://dx.doi.org/10.1182/blood-2023-179960.
Full textAbstract:
Background: PNH is an ultrarare disease characterized by complement-mediated hemolysis and subsequent anemia, bone marrow failure and thrombosis. In pts not treated with complement inhibitors, intravascular hemolysis (IVH) results from unregulated progression of the complement system and membrane attack complex formation. IVH is controlled in pts treated with anti-C5 therapy, but extravascular hemolysis (EVH) may emerge and cause persistent anemia. High LDH levels are a marker of ongoing IVH, while anemia can result from both IVH and EVH. Iptacopan is the first oral proximal complement inhibitor targeting factor B to selectively inhibit the alternative pathway of the complement cascade. As shown in PNH Phase III trials (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04820530]), iptacopan can achieve good control of hemolysis. Aim: To support the dose selection for iptacopan, this analysis characterizes the exposure-response relationships between iptacopan and efficacy measures (LDH and Hb) in pts with PNH. The effect of prior anti-C5 treatment status has also been evaluated. Methods: This analysis is based on data from 4 clinical trials enrolling pts with PNH.Final data were used from the completed Phase II trials X2201 (NCT03439839; pts with active hemolysis despite anti-C5 therapy received concomitant iptacopan) and X2204 (NCT03896152; anti-C5-naïve pts received iptacopan monotherapy), in which iptacopan was administered orally in doses ranging from 25 to 200 mg twice daily (bid). Data up to the cut-off dates of 26 September 2022 and 2 November 2022 were used from the Phase III trials, APPLY-PNH (pts previously treated with anti-C5) and APPOINT-PNH (pts not treated with complement inhibitors including anti-C5), respectively, in which oral iptacopan was administered at 200 mg bid. A longitudinal mixed-effects modeling approach was applied to LDH and Hb. To account for the delay between exposure and response, indirect response models were developed for LDH and Hb. The models were used to predict the long-term (6 months) LDH and Hb responses for various iptacopan bid dose levels and to estimate (using simulation) the proportion of pts achieving LDH ≤1.5 × upper limit of normal (ULN) and Hb ≥12 g/dL. Results: The modeling dataset contained 161 pts with PNH; 94 (58%) were female, and median (range) age was 45 (18-84) years. For modeling of LDH and Hb levels, 2812 and 2587 samples were used, respectively, as well as 1577 pharmacokinetic samples. In total, 53 (33%) pts had not received anti-C5 treatment. Of the remaining 108 pts, 16 (15%) received iptacopan as add-on therapy to anti-C5 (pts from X2201) and 92 (85%) had previously received anti-C5 (pts from APPLY-PNH). The indirect response models were considered biologically plausible and adequately described the data using a common EC 50 value to both anti-C5-naïve pts and pts currently receiving or who previously received anti-C5. The estimated concentration of iptacopan required to achieve 90% of the maximum response (EC 90) of LDH was 268 ng/mL (90% confidence interval [CI] 238, 302), irrespective of prior anti-C5 treatment status ( Figure). The estimated typical LDH value after iptacopan treatment at an exposure &gt;EC 90 was 237 U/L (90% CI 224, 250) within the normal LDH range (&lt;250 U/L). Iptacopan 200 mg bid was the dose at which the highest proportion of pts (86%) achieved LDH ≤1.5 × ULN. While baseline LDH levels differed between anti-C5-naïve pts and pts currently receiving or who previously received anti-C5, similar proportions of these pts achieved LDH ≤1.5 × ULN (84% and 88%, respectively). The estimated EC 90 of Hb ≥12 g/dL was 1968 ng/mL (90% CI 1661, 2333) ( Figure); 89% of all pts were expected to reach EC 90 exposure at iptacopan 200 mg bid. The estimated Hb value after treatment with iptacopan at an exposure &gt;EC 90 was 12.7 g/dL (90% CI 12.4, 13.0). 70% of pts were expected to achieve Hb normalization (≥12 g/dL) with iptacopan 200 mg bid. Similar proportions of anti-C5-naïve pts and pts who were currently receiving or who previously received anti-C5 achieved Hb ≥12 g/dL (71% and 68%, respectively). Conclusions: Indirect response models were developed to describe the exposure-response relationships between iptacopan and efficacy measures (LDH and Hb) in pts with PNH. The analysis demonstrated that 200 mg bid is the dose of oral iptacopan that achieves LDH ≤1.5 × ULN and Hb normalization in the highest proportion of patients regardless of prior treatment status.
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Baltcheva, Irina, Christian Bartels, Marie-Anne Valentin, Robert Schmouder, Guido Junge, and Jing Yu. "Exposure-Response Relationships between the Factor B Inhibitor Iptacopan and Complement Biomarkers in Healthy Volunteers and Patients (Pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH), C3 Glomerulopathy (C3G) or IgA Nephropathy (IgAN)." Blood 142, Supplement 1 (2023): 5640. http://dx.doi.org/10.1182/blood-2023-180004.
Full textAbstract:
Background: Iptacopan is the first oral proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway (AP) of the complement system. Iptacopan is currently being investigated in Phase III trials in PNH, C3G and IgAN. AP biomarkers can be used to evaluate the inhibitory effect of iptacopan. Wieslab ® ex vivo assay measures the amount of soluble C5b-9 (sC5b-9) formation in serum after AP activation. Plasma sC5b-9 is the final product of complement activation and is also known as the membrane attack complex. Plasma Bb levels increase following AP activation. Aim: To characterize exposure-response relationships between iptacopan and AP biomarkers Wieslab ®, Bb and sC5b-9 to rationalize the iptacopan dose selection. Methods: This analysis was based on final data from a Phase I clinical trial enrolling healthy volunteers (X2101 [EUDRACT2015-005567-16]) and 4 Phase II trials enrolling pts with PNH (X2201 [NCT03439839] and X2204 [NCT03896152]), C3G (X2202 [NCT03832114]) and IgAN (X2203 [NCT03373461]). In these trials, oral iptacopan was administered in doses ranging from 5-400 mg single dose and from 10-200 mg twice daily (bid). A longitudinal mixed-effects modeling approach was applied to the AP biomarkers used in this study: serum Wieslab ® assay, plasma Bb and plasma sC5b-9. Direct response sigmoid Emax models were considered as most appropriate and biologically plausible for all biomarkers, reflecting the rapid biomarker response following exposure to iptacopan. The exposure metric driving the response was the observed time-matching pharmacokinetic (PK) data. A population PK (popPK) model built on bid dose levels (10-200 mg) using data from pts (not healthy volunteers) simulated steady state exposure over 6 months of iptacopan bid dosing in each population. Results: The modeling dataset contained 247 participants, of which 88 (36%) were healthy volunteers, 29 (12%) were pts with PNH, 27 (11%) were pts with C3G, and 103 (42%) were pts with IgAN. Overall, 69 (28%) participants were female, and the median age (range) was 38 (18-78) years. A total of 2317, 2296 and 2279 samples for Wieslab ®, Bb and C5b-9, respectively, were used in the modeling, with the same number of time-matched PK samples. The biomarker responses decreased monotonically with saturation of effect and without apparent time lag, which was expected based on the mechanism of iptacopan. An exposure-dependent decrease in Wieslab ® was seen in pts and healthy volunteers, with estimated iptacopan concentrations required to achieve 90% of the maximum response (EC 90) being 1281 ng/mL (90% confidence interval [CI] 1207, 1418) and 706 ng/mL (90% CI 653, 788), respectively. Based on simulations from the popPK model, this exposure was expected to be reached at steady state trough concentration (C trough) by an estimated 74% of pts at 200 iptacopan mg bid, compared with 44% and 18% receiving 100 mg bid and 50 mg bid, respectively ( Table). The interindividual variability of Wieslab ® response decreased as iptacopan dose increased to 200 mg bid and C trough to ≥1300g/mL. A clear decrease from baseline in plasma Bb was seen following iptacopan treatment, with an EC 90 value of 521 ng/mL (90% CI 268, 912). Based on simulations from the popPK model, this exposure was expected to be reached by 97% of pts treated with iptacopan 200 mg bid, compared with 91% and 79% receiving 100 mg bid and 50 mg bid, respectively ( Table). For sC5b-9, the EC 90 value was 682 ng/mL (90% CI 503, 894) across all participants. This exposure was expected to be achieved by 94%, 83% and 64% of pts receiving iptacopan 200 mg bid, 100 mg bid and 50 mg bid, respectively ( Table). Age, weight, sex and ethnicity did not affect the biomarker responses. Conclusions: In this analysis, iptacopan 200 mg bid was the dose at which the highest proportion of participants achieved EC 90 values for the AP biomarkers Wieslab ®, Bb and sC5b9. Other than pts having higher EC 90 values than healthy volunteers for Wieslab ®, no differences were found in EC 90 values between the trial populations, demonstrating that no dose adjustment is needed between them. A response plateau was achieved by the iptacopan 200 mg bid dose for Wieslab ® and lower doses for Bb and C5b-9, suggesting higher doses would not lead to greater responses. In summary, these data support the use of oral iptacopan at 200 mg bid to achieve rapid, substantial and sustained inhibition of the complement AP in pts with PNH, C3G or IgAN.
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Peffault De Latour, Regis, Austin Kulasekararaj, Phillip Scheinberg, et al. "Clinical Breakthrough Hemolysis (BTH) during Monotherapy with the Oral Factor B Inhibitor Iptacopan Is Generally Not Severe and Managed without Treatment Discontinuation: 48-Week Data from the Phase III Apply-PNH and Appoint-PNH Trials in Paroxysmal Nocturnal Hemoglobinuria (PNH)." Blood 142, Supplement 1 (2023): 1338. http://dx.doi.org/10.1182/blood-2023-179377.
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Background: In PNH, BTH is characterized by the re-emergence of intravascular hemolysis (IVH) despite ongoing complement inhibition and is recognized by the reappearance of IVH/PNH signs/symptoms, coupled with a marked increase in lactate dehydrogenase (LDH) and sharp decrease in hemoglobin (Hb). Iptacopan is the first oral proximal complement inhibitor targeting factor B in the alternative pathway and has shown efficacy and safety in complement inhibitor-naïve PNH patients (pts; APPOINT-PNH; NCT04820530) and pts with persistent anemia despite anti-C5 treatment (APPLY-PNH; NCT04558918). In the APPLY-PNH 24-week (wk) analysis, iptacopan monotherapy showed superiority in the adjusted annualized rate of clinical BTH vs C5 inhibitors. Aim: We report the proportion of pts with clinical BTH, exposure-adjusted occurrence rates and BTH characteristics during iptacopan monotherapy in the Phase III APPLY-PNH and APPOINT-PNH trials (study completion [48-wk data]: 6 March and 18 April 2023, respectively). Methods: The prespecified protocol criteria for clinical BTH were LDH &gt;1.5 × upper limit of normal (ULN) and increased vs the last 2 assessments, plus a ≥2 g/dL Hb decrease (vs the last assessment or within 15 days) or significant PNH signs/symptoms. All BTH was classed as an adverse event and evaluated for severity (investigator assessment) and seriousness (per protocol). In APPLY-PNH, adults who had received anti-C5 therapy for ≥6 months and had mean Hb &lt;10 g/dL were randomized to receive oral iptacopan 200 mg twice daily or continue their anti-C5 regimen for 24 wks (randomized treatment period [RTP]). In APPOINT-PNH, adult complement inhibitor-naïve pts with mean Hb &lt;10 g/dL and mean LDH &gt;1.5 × ULN received iptacopan 200 mg twice daily for 24 wks. Both trials then had extension periods in which all pts could receive iptacopan monotherapy for another 24 wks. Results: In APPLY-PNH, 61/62 pts in the iptacopan arm continued iptacopan in the extension period and 34/35 in the anti-C5 arm switched to iptacopan. All 40 pts in APPOINT-PNH entered the extension period. When these 48-wk trials completed, 136 pts had received iptacopan with varying exposure (total exposure ~111 pt-years), of whom 9 had clinical BTH (10 events, Table). Two pts were in APPOINT-PNH (2/40, 2 events) and 7 in APPLY-PNH (7/96, 8 events). Of the iptacopan-treated pts in APPLY-PNH, 2 had BTH in the RTP; 1 of these pts plus 5 others had BTH in the extension period (including 1 who switched from anti-C5 to iptacopan at Wk 24). The exposure-adjusted occurrence rate of clinical BTH on iptacopan was 11.0 events per 100 pt-years in APPLY-PNH (95% confidence interval [CI] 5.2‒23.3) and 5.2 events per 100 pt-years in APPOINT-PNH (95% CI 1.3‒20.5). In the 24-wk APPLY-PNH RTP, 6/35 pts in the anti-C5 arm had clinical BTH (11 events); the exposure-adjusted occurrence rate was 66.9 events per 100 pt-years (95% CI 25.0‒178.9), which is &gt;6 times higher than the rates on iptacopan. Of the 10 clinical BTH events reported on iptacopan, all were mild or moderate except 1 severe (and serious) event despite large PNH RBC clone sizes of &gt;90% reported before 5/8 events with available clone size data. The impact of BTH on Hb was generally transient (Figure). Potential complement-amplifying conditions (CACs) were identified for 8 clinical BTH events during iptacopan treatment; the severe event was associated with COVID-19 and the temporal appearance of cold agglutinins. No pts discontinued iptacopan because of clinical BTH. RBC transfusions were the most common intervention; 1 pt received a 900 mg dose of eculizumab. In the anti-C5 arm in the APPLY-PNH RTP, 1/11 BTH events was severe and 2/11 were associated with potential CACs. Conclusions: In Phase III trials, 136 PNH pts received iptacopan monotherapy and few pts had clinical BTH, with severity being comparable to that with anti-C5 despite PNH RBC clone sizes &gt;90%. Most clinical BTH events on iptacopan were associated with potential CACs; BTH was manageable with no intervention or RBC transfusion and without iptacopan discontinuation. The exposure-adjusted occurrence rates support our prior finding of a significantly lower adjusted annualized rate of clinical BTH with iptacopan vs anti-C5. BTH must be monitored with any complement inhibitor, but these data show that BTH was infrequent on iptacopan and support the positive safety profile of proximal complement inhibition with oral iptacopan monotherapy in hemolytic PNH.
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Ito, Satoko, Karthik Chetlapalli, Kunal C. Potnis, et al. "Setting Cost-Effective Price Thresholds before FDA Approval: Cost-Effectiveness of Iptacopan Monotherapy Versus Standard-of-Care Anti-C5 Therapy in Transfusion-Dependent, Treatment-Experienced Adult Patients with Paroxysmal Nocturnal Hemoglobinuria in the United States." Blood 142, Supplement 1 (2023): 5042. http://dx.doi.org/10.1182/blood-2023-188063.
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Introduction: Oral complement inhibition therapy has the potential to transform the care of patients with paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening hematological disorder characterized by intravascular hemolysis, thrombosis, and bone marrow failure. Current standard-of-care (SOC) for PNH are monoclonal antibodies targeting the distal complement component 5 (C5) and include the intravenous agents eculizumab and ravulizumab. However, this distal mechanism of action allows extravascular hemolysis to persist. Intravenous therapy also requires patient and nursing time spent for infusion care. Iptacopan is one oral proximal complement pathway inhibitor that selectively inhibits complement factor B. Clinical trial data shows that iptacopan controls both intravascular and extravascular hemolysis, resulting in increased transfusion independence. Iptacopan was granted breakthrough therapy designation for expedited review by the FDA. The potential approval is anticipated by the end of 2023, after which point pricing will be set. A cost-effective price for iptacopan is currently not known. We sought to fill this gap by conducting the first cost-effectiveness analysis of oral versus intravenous complement inhibitor therapy in PNH to determine a cost-effective monthly price threshold for iptacopan monotherapy and to estimate patient and nursing time saved with transition to oral therapy. Methods: In this independent analysis free of industry influence, we built a Markov model to first determine the cost-effectiveness of iptacopan monotherapy at a monthly cost equivalent to SOC. Second, we solved for the cost-effective monthly maximum threshold cost of iptacopan across accepted willingness-to-pay thresholds in US dollars per quality-adjusted life-year (QALY). Transition probabilities for transfusion burden and breakthrough hemolysis were informed by the phase III study results (NCT 04558918). Probabilities of transfusion-associated adverse events were sourced from hemovigilance reporting in the 2015 National Blood Collection and Utilization Survey. Costs were assessed in 2023 US dollars and were informed from the Centers for Medicare & Medicaid Services and PNH-specific health resource utilization literature. The latter accounted for country- and PNH-specific direct and indirect medical costs, derived after adjustment for baseline characteristics, and isolated for transfusion-dependent treatment-experienced patients with PNH by comparison to transfusion-independent, treatment-experienced patients with PNH. Effectiveness was calculated in quality-adjusted life-years (QALY), and employed PNH-specific utilities. The two primary outcomes for iptacopan monotherapy were 1) the incremental cost-effectiveness ratio (ICER) or, the incremental net monetary benefit (iNMB) if the therapy was found to be cost saving, and 2) the cost-effective maximum monthly threshold price of iptacopan monotherapy, as compared to the SOC. The secondary outcome was the aggregated patient and nursing time saved with the use of oral versus intravenous treatment. We concluded with deterministic sensitivity analysis to isolate parameters that the model results are most sensitive to, and probabilistic sensitivity analysis to capture uncertainty in all parameters simultaneously over 10,000 Monte Carlo simulations. Results: In the base-case (i.e., where monthly price of iptacopan is equivalent to SOC), therapy with iptacopan versus C5 inhibition accrued 15.6 and 13.5 QALYs at costs of $9.7 million and $14.0 million, respectively. The iNMB with iptacopan was $4.4 million (95% credible interval $2.7-6.5 million) and threshold analysis for the maximum monthly price of iptacopan was $61,000. Iptacopan therapy projects to save patients and nurses approximately 730 and 2920 hours for ravulizumab and eculizumab, respectively, in PNH-specific care averted. Model results were most sensitive to iptacopan price. Conclusion: If the monthly price is no more than 149% of SOC, iptacopan monotherapy can be a cost-effective therapeutic option for transfusion-dependent, treatment-experienced patients with PNH. This is achieved by increasing the proportion of transfusion-independence in this patient population and, in turn, decreasing the burden of both the risks and costs associated with health resource utilization for patients with PNH.
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Schmouder, Robert L., Melissa Hackling, Bharti Shah, S. Eralp Bellibas, and Kenneth Kulmatycki. "Multiple Supratherapeutic Doses of Iptacopan 400 Mg Twice Daily Are Well Tolerated in Healthy Participants: Safety Findings from a Randomized, Participant-Blinded, Placebo-Controlled, Phase I Study." Blood 144, Supplement 1 (2024): 5670. https://doi.org/10.1182/blood-2024-198628.
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Background: Iptacopan, the first oral proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement system, is approved as a monotherapy for adults with paroxysmal nocturnal hemoglobinuria and is being investigated in diseases such as immunoglobulin A nephropathy, C3 glomerulopathy and atypical hemolytic uremic syndrome. Iptacopan is administered at a therapeutic dose of 200 mg twice daily (bid). A Phase I, randomized, participant-blinded, placebo-controlled study (A2109) is being conducted to assess the safety, pharmacokinetics and pharmacodynamics of multiple supratherapeutic oral doses of iptacopan (400 mg and 800 mg bid) in healthy volunteers. Aim: To report the safety findings from the completed Cohort 1 of the ongoing A2109 study, in which healthy participants received multiple 400 mg bid supratherapeutic doses of iptacopan or placebo. Methods: Healthy individuals aged between 18 and 55 years were enrolled into Cohort 1 and were randomized 2:1 to receive iptacopan 400 mg bid or matching placebo. There was a 28-day screening period, a 14-day treatment period and a 5-day post-treatment washout period. The primary endpoint was safety, including adverse event (AE) reportings, vital signs, electrocardiogram (ECG) assessments and safety laboratory evaluations. Pre-dose safety data were collected at screening and baseline. On treatment, safety laboratory evaluations were performed on Days 2, 3, 7, 10, 14, 15, 16, 18 and 19; vital signs were measured daily; and ECG assessments were done on Days 1, 4, 7, 10, 14 and 19. Results: Twelve healthy volunteers were enrolled into Cohort 1; 8 received iptacopan 400 mg bid and 4 received placebo.Two participants in the iptacopan arm had AEs during the treatment period; 1 had moderate headache and the other had a mild AE of elevated amylase levels. These 2 AEs were considered related to iptacopan; however, both resolved without the need for additional treatment. No participants discontinued iptacopan. One individual receiving placebo had 5 mild AEs during the treatment period (chills, bilateral hand pain, sensation of feeling flushed, headache and bilateral sclera erythema), which resolved without the need to discontinue treatment. The other 3 participants who received placebo had no AEs. During iptacopan treatment, there was no evidence of an effect on any laboratory parameter (including red or white blood cell count), ECG parameter or vital sign (including heart rate and blood pressure), and there was no adverse impact on liver, kidney or thyroid function. Conclusions: Multiple supratherapeutic doses of iptacopan 400 mg bid for 14 days were well tolerated in healthy individuals. Based on these results, the study will progress to assess iptacopan 800 mg bid in Cohort 2.
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Zhang, Fengkui, Li Zhang, Chen Yang, et al. "KP104, a Bifunctional C5 Mab-Factor H Fusion Protein, Demonstrates Sustained Long-Term Efficacy and Safety in Complement Inhibitor-Naïve PNH Patients: Updated Results from a Phase 2 Study at 36/38 Weeks of Obd Treatment." Blood 144, Supplement 1 (2024): 2699. https://doi.org/10.1182/blood-2024-210086.
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Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic condition marked by intravascular and extravascular hemolysis (IVH and EVH), driven by the complement terminal and proximal effectors of the alternative pathway, respectively. KP104, a novel bifunctional recombinant fusion protein comprised of a humanized anti-C5 mAb and the functional domain of complement regulator factor H, can simultaneously inhibit both terminal and proximal complement activations. We previously reported data from an ongoing Phase II study (NCT05476887) involving 18 complement inhibitor-naïve PNH patients treated with KP104 for ≥24/26 weeks at the Optimal Biological Dose (OBD). KP104 demonstrated a favorable safety and efficacy profile, achieving effective control of both IVH and EVH as evidenced by rapid and sustained normalization or near-normalization of lactate dehydrogenase (LDH) levels, significant improvement in hemoglobin (Hgb) levels, complete avoidance of blood transfusions, and clinically meaningful enhancements in FACIT-Fatigue scores (Han, EHA 2024). Aims: We present updated long-term data from this ongoing Phase II trial. As of the data cutoff date of May 23, 2024, all patients had received KP104 at OBD for ≥36/38 weeks, with a total treatment duration of 53-77 weeks. Results from ≥48 weeks of treatment at OBD will become available in September 2024 and be included in the meeting presentation. Methods: A total of 18 complement inhibitor-naïve PNH patients were enrolled in three dose-ascending cohorts, with 6 patients per cohort. After completing 12/13 weeks of the primary treatment phase, all patients entered a long-term extension phase, during which they transitioned from their starting dose to a weight-tiered OBD regimen: 1,920 mg SC Q2W for those weighing 45-79 kg and 2,400 mg SC Q2W for those weighing 80-120 kg. Results: Substantial clinical improvements observed at ≥24/26 weeks post-OBD treatment were sustained through ≥36/38 weeks post-OBD in all patients. As of the data cutoff, 100% (18/18) of patients maintained a Hgb increase of ≥2 g/dL from baseline, with mean (SD) Hgb levels reaching an average of 13.1 (2.0) g/dL and a 6.2 (2.1) g/dL improvement from baseline. Additionally, 83.3% (15/18) of patients achieved Hgb normalization (≥12 g/dL). LDH levels of &lt;1.5x ULN were sustained in 94.4% (17/18) of patients, with normal or near-normal LDH. Moreover, 100% (18/18) of patients remained free from red blood cell transfusions and 88.9% (16/18) avoided breakthrough hemolysis (BTH). KP104 continued to be safe and well-tolerated, with no serious adverse events or treatment-emergent adverse events (TEAEs) leading to drug discontinuation or study withdrawal. No new safety signals were identified. All 18 patients remained free from major adverse vascular events, and no severe adverse events were reported. The most frequently reported TEAEs to date were COVID-19 (38.9%), injection site induration (27.8%), hyperuricemia (16.7%), hyperlipidemia (11.1%), headache (11.1%), nasopharyngitis (11.1%), influenza (11.1%), and influenza-like illness (11.1%). Two cases of BTH were observed during the study. The first case, associated with gastroenteritis, occurred at the lowest starting dose cohort before the transition to OBD. After switching to OBD, the patient remained free of BTH. The second case of BTH occurred in a patient with co-existing myeloproliferative neoplasms (MPN). Conclusion: The long-term results from this Phase II study of 53-77 weeks of KP104 treatment, including ≥36/38 weeks at OBD, demonstrate sustained clinical benefits and a favorable safety profile, affirming the durable efficacy of KP104 in controlling both intravascular and extravascular hemolysis in complement inhibitor-naïve PNH patients. The data continue to provide compelling clinical evidence to support the development of KP104 as a novel first-line monotherapy option for PNH patients with desired efficacy and safety (Notaro & Luzzatto, NEJM 2022).
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Peffault De Latour, Regis, Austin G. Kulasekararaj, Phillip Scheinberg, et al. "The Effect of Oral Iptacopan Monotherapy on Hematological Parameters in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Is Consistent Regardless of the Type of Prior Anti-C5 Treatment Received: A Post Hoc Analysis of 24-Week Data from the Randomized Phase III APPLY-PNH Trial." Blood 144, Supplement 1 (2024): 4087. https://doi.org/10.1182/blood-2024-200763.
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Background: Iptacopan, an oral proximal complement inhibitor that targets factor B, is approved as a monotherapy for the treatment of adults with PNH based on the results of 2 Phase III trials (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04820530]). APPLY-PNH enrolled patients with PNH that were receiving either intravenous eculizumab or ravulizumab. Both treatments inhibit C5; however, ravulizumab has an extended half-life, allowing dosing every 8 weeks compared with eculizumab, which is dosed every 2 weeks. In APPLY-PNH, 24 weeks of iptacopan monotherapy was superior to anti-C5 treatment across a range of outcomes, including clinically meaningful hemoglobin (Hb) increases, Hb ≥12 g/dL and changes from baseline in Hb and absolute reticulocyte count (ARC). We performed a post hoc analysis to explore whether the type of anti-C5 treatment received prior to randomization (eculizumab or ravulizumab) affected hematological parameters and response to iptacopan monotherapy in the randomized treatment period of APPLY-PNH. Methods: Adult PNH patients with mean Hb &lt;10 g/dL receiving a stable regimen of eculizumab or ravulizumab for ≥6 months were enrolled in APPLY-PNH. Patients were randomized 8:5 to receive iptacopan monotherapy 200 mg twice daily or to continue their anti-C5 regimen for 24 weeks. We performed a post hoc analysis in which mean changes from baseline for Hb and ARC and geometric mean ratio to baseline for lactate dehydrogenase (LDH) at each visit were presented according to whether the patient received eculizumab (eculizumab subgroup) or ravulizumab (ravulizumab subgroup) prior to randomization. Results: In APPLY-PNH, 62 patients were randomized to the iptacopan arm, 40 of whom had received eculizumab prior to randomization and 22 had received ravulizumab. Mean Hb at baseline was 9.0 (standard deviation [SD] 0.7) and 8.8 (SD 0.7) g/dL in the eculizumab and ravulizumab subgroups, respectively. Increases from baseline in Hb were comparable in both subgroups of the iptacopan arm at each individual visit during the randomized treatment period, with a 3.8 (SD 1.3) g/dL increase from baseline to Week 24 in the eculizumab subgroup and a 3.5 (SD 1.3) g/dL increase in the ravulizumab subgroup. At baseline, mean ARC was 198.9 (SD 87.4) × 109/L in the eculizumab subgroup and 183.0 (SD 77.2) × 109/L in the ravulizumab subgroup. Reductions in mean ARC were consistent between the subgroups in the iptacopan arm at each visit in the randomized treatment period; at Week 24, mean changes from baseline in ARC were −122.0 [SD 65.1] and −116.7 [SD 65.4] × 109/L in the eculizumab and ravulizumab subgroups, respectively, reaching mean levels in the normal range. Mean LDH at baseline was 265.6 (SD 70.0) and 275.5 (SD 71.6) U/L in the eculizumab and ravulizumab subgroups, respectively. LDH in both subgroups remained low throughout the randomized treatment period of APPLY-PNH, and the geometric mean ratio to baseline in the 2 subgroups of the iptacopan arm were consistent at each visit. At Week 24, the geometric mean ratio to baseline in LDH (U/L) was 1.0 in the eculizumab subgroup and 1.0 in the ravulizumab subgroup. When plotted graphically, mean changes from baseline in Hb and ARC and geometric mean ratio to baseline in LDH for the eculizumab and ravulizumab subgroups of iptacopan-treated patients were generally superimposable throughout the randomized treatment period. Results for all 3 parameters in the 35 patients randomized to continue anti-C5 treatment in APPLY-PNH were also consistent regardless of whether they were receiving eculizumab (23 patients) or ravulizumab (12 patients). Conclusions: This post hoc analysis found that the improvements achieved in Hb and ARC in the iptacopan arm of APPLY-PNH were consistent regardless of the anti-C5 regimen patients with PNH received prior to randomization. LDH also remained similar to baseline throughout the randomized treatment period for both subgroups of the iptacopan arm. These results show that, despite the different pharmacokinetic profiles of eculizumab and ravulizumab, there was no difference between the 2 subgroups in the time courses of change from baseline in Hb and ARC and geometric mean ratio to baseline in LDH with iptacopan monotherapy, indicating that iptacopan was effective regardless of which C5 inhibitor patients with PNH received before randomization in the APPLY-PNH trial.
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Peffault de Latour, Regis, Alexander Roeth, Austin Kulasekararaj, et al. "Oral Monotherapy with Iptacopan, a Proximal Complement Inhibitor of Factor B, Has Superior Efficacy to Intravenous Terminal Complement Inhibition with Standard of Care Eculizumab or Ravulizumab and Favorable Safety in Patients with Paroxysmal Nocturnal Hemoglobinuria and Residual Anemia: Results from the Randomized, Active-Comparator-Controlled, Open-Label, Multicenter, Phase III Apply-PNH Study." Blood 140, Supplement 2 (2022): LBA—2—LBA—2. http://dx.doi.org/10.1182/blood-2022-171469.
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Morado-Arias, Marta, Monica Ballesteros, Miguel Gómez-Álvarez, Federico Herrera, and Ana Villegas. "Response to Pegcetacoplan in Patients with PNH Assessed By Erythroid Clonal Size and Laboratory Markers." Blood 144, Supplement 1 (2024): 5679. https://doi.org/10.1182/blood-2024-203498.
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Introduction: Pegcetacoplan (PEG) is a proximal complement inhibitor used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH). By blocking the complement at C3 level, it inhibits intravascular hemolysis without inducing extravascular hemolysis due to C3 deposition, a typical side effect of C5 inhibitors (C5i). This mechanism of action explains its greater effectiveness in controlling anemia compared to terminal inhibitors. Response criteria to PEG can be assessed using laboratory markers of hemolysis as well as erythroid clonal size, which increases to achieve the same size as in leukocytes. Aim: The aim of this study is to analyze the timing and degree of response to PEG treatment in PNH patients who have switched from C5i in the autonomous region of Madrid (Spain). Response is assessed using easily accessible laboratory markers such as hemoglobin (Hb-g//dL), absolute reticulocytes (Ret-x10e9/L), lactate dehydrogenase (LDH, ratio with upper limit of normal-ULN) and bilirubin (Br-mg/dL). We specifically focus on PNH-red cell clone size (RC-c) and its kinetics of increase, compared to PNH-granulocyte clone (Gr-c), using the RC-c/Gr-c ratio. Results and discussion: Four patients (2 male/2 female) with ages between 24 and 61 years (median: 47) were diagnosed with PNH, two of them associated with aplastic anemia and myelodysplastic syndrome. Laboratory parameters and clonal size (median/range) at diagnosis were Hb:7.8/4.8-14.4; Ret 273/117-510; LDH: 9.00/1.08-14; Br: 1.5/1.2-2.3; Gr-c: 98.2%/16-99.7; RC-c: 49.1%/22.6-75.6; RC-c/Gr-c ratio: 0.5. All patients were treated with C5i for 48 months (3-82) and subsequently changed to PEG due to persistent DAT-positive anemia for C3d. Pre-PEG parameters were: Hb:9.6/9.1-10.5; Ret 301/268-333; LDH: 1.07/1.04-1.27; Br: 2.2/1.3-3.4; Gr-c: 97%/94-99.8; RC-c: 48.7%/29-68.5; RC-c/Gr-c ratio: 0.5. One month after switching, all laboratory parameters normalized, without anemia (Hb:12.8/12.6-14.4), reticulocytosis (Ret 64/47-98) or other signs of hemolysis (Br: 0.6/0.3-0.8), including LDH levels lower than ULN (0.75/0.70-0.80). Response to PEG was maintained in all patients at 3 months (Hb:12.8/12-13.5; Ret 123/87-150; LDH: 1.00/0.84-1.10; Br: 0.7/0.6-1.1) and in those two who achieved 12 months of follow-up (Hb:12/11.8-12; Ret 101/63-140; LDH: 1.01/1.00-1.03; BR: 0.7/0.7-0.8). Regarding RC-c size, a significant increase was observed after one month of PEG treatment (RC-c: 99%/86.3-99.4), reaching a similar Gr-c size (RC-c/Gr-c ratio:1) or slightly lower at 3 months (RC-c: 94.8%/93.5-95.6; RC-c/Gr-c ratio:0.97), and at 6 months (RC-c: 96.1%/96-96.1; RC-c/Gr-c ratio: 0.98). Beyond 9 months of PEG treatment, RC-c size remained at a similar level in one patient (RC-c: 95.8%/Ratio: 0.96) but slightly decreased in the other one (RC-c: 77,7%/Ratio: 0.78) in the context of viral infection without clinical or analytical impact, with progressive recovery one month later (RC-c: 83%). No acute clinical breakthrough hemolysis, or relevant side effects were communicated during PEG treatment. Conclusions: After switching from iC5, PEG quickly increases Hb to normal values without evidence of signs of hemolysis as soon as one month after treatment. RC-c approaches Gr-c size from the first month onwards. The combination of laboratory markers and RC-c size allows correct monitoring of the response to PEG. Subtle reductions of RC-c could be detected after minor infections, serving as early predictive markers of a potentially relevant hemolysis.
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Karnabeda, Oksana, Valentyn Moskalenko, Zoreslava Lysak, et al. "OMS906, a Novel Alternative Pathway MASP-3 Inhibitor, Normalizes Hemoglobin Levels and Increases Clone Size in Treatment-Naïve PNH Patients." Blood 142, Supplement 1 (2023): 573. http://dx.doi.org/10.1182/blood-2023-177921.
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Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disorder characterized by hemolytic anemia in combination with various degrees of marrow failure. PNH is driven by dysregulation of the complement system where the absence of CD55 and CD59 cell surface proteins leads to red blood cell (RBC) lysis. Untreated PNH can lead to debilitating anemia, thrombosis, fatigue, and increased mortality. Terminal complement inhibition attenuates intravascular hemolysis (IVH) but inevitably leads to extravascular hemolysis (EVH). Proximal and alternative pathway (AP) inhibition block both IVH and EVH, as demonstrated with C3, Factor B, and Factor D inhibitors. Mannan-binding lectin-associated serine protease-3 (MASP-3) activates pro-Factor D, thus activating the AP upstream of Factor D. OMS906 is a highly selective humanized mAb that binds to and inhibits MASP-3. In a Phase 1 study in healthy subjects, OMS906 was well tolerated and provided substantial MASP-3 inhibition. In the present study, safety and efficacy of OMS906 were evaluated in complement-inhibitor treatment-naïve patients with PNH. Methods: This is an ongoing, single-arm, open-label, Phase 1b proof-of-concept clinical trial (NCT05889299; EudraCT 2022-002450-22) evaluating safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of OMS906 in adults with PNH. Eligibility criteria include: confirmed PNH diagnosis by flow cytometry (RBC clone size &gt;10%); complement-inhibitor treatment-naïve or inadequate response to C5 inhibitors; and baseline hemoglobin (Hgb) &lt;10.5 g/dL. Patients received 5 mg/kg subcutaneous (SC) OMS906 every 4 weeks, the lowest exposure cohort in this study. Primary endpoints are safety and tolerability. Secondary endpoints include changes from baseline in Hgb and lactate dehydrogenase (LDH) levels, RBC clone size, and absolute reticulocyte count; achievement of Hgb ≥12 g/dL or an increase of ≥2 g/dL; and transfusion independence. Planned enrollment was approximately 10 patients. Results: This pre-specified interim analysis included data available as of July 20, 2023. All patients (N=11) included in this analysis were complement-inhibitor treatment-naïve (55% female; mean age 41 years [range 27-72]). The majority of patients (64%) received RBC transfusions in the 12 months prior to OMS906 treatment. Co-existing conditions included iron deficiency (n=6), chronic renal failure (n=3), aplastic anemia (n=2), and myelodysplastic syndrome (MDS; n=2). At baseline (N=11), mean Hgb was 7.0 g/dL (median 6.4 g/dL, range 3.9-10.4 g/dL) and LDH was 1835 U/L (median 1831 U/L, range 905-3480). To date, all patients have received ≥2 doses of OMS906 with 4 patients having received ≥6 doses. OMS906 was well tolerated. The most common adverse events (AEs) in ≥20% of patients were increased thrombocytopenia (36%), neutropenia (27%), and itching (27%). No patients experienced clinical breakthrough hemolysis. There were no major adverse vascular events, treatment-related serious AEs, discontinuations, or deaths. Following initiation of OMS906, mean Hgb increased from baseline by 3.1 g/dL ( P&lt;0.001) at 4 weeks (N=11), and by 9.5 g/dL ( P=0.016) at the latest timepoint of 24 weeks (n=3) [Figure 1]. Among patients receiving ≥2 doses, all but 3 experienced gender-specific normalization of Hgb levels. The remaining patients had MDS (n=2) or marrow failure (n=1). No patients required transfusions following OMS906 treatment. Mean LDH levels decreased from baseline by 1483 U/L (&gt;80%; P&lt;0.001) at 4 weeks (N=11) and by 1939 U/L ( P=0.004) at 24 weeks (n=3). Three patients had increases in LDH, suggesting initiation of hemolysis at the end of a dosing period. Mean absolute reticulocyte counts decreased from baseline by 87,000-122,000 ×10 9/L at all timepoints. Mean PNH RBC clone size increased by up to 38.6% (n=6; P=0.016) versus baseline. Conclusion: In this interim analysis, MASP-3 inhibitor OMS906 was well tolerated with no safety signals of concern. Once-monthly SC OMS906 resulted in clinically meaningful, beneficial effects on Hgb, LDH, and RBC clone size in treatment-naïve PNH patients. OMS906 dose escalation guided by occurrence of subclinical hemolysis is being evaluated with the goal of achieving quarterly dosing.
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Risitano, Antonio M., Austin Kulasekararaj, Alexander Roeth, et al. "Factor B Inhibition with Oral Iptacopan Monotherapy Demonstrates Sustained Long-Term Efficacy and Safety in Anti-C5-Treated Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia: Final 48-Week Results from the Multicenter, Phase III APPLY-PNH Trial." Blood 142, Supplement 1 (2023): 571. http://dx.doi.org/10.1182/blood-2023-180780.
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Drs Roeth and Kulasekararaj contributed equally as authors. Background: Iptacopan is the first oral complement inhibitor that acts proximally in the complement system to target factor B in the alternative pathway. Iptacopan has shown efficacy/safety in PNH pts with persistent anemia despite anti-C5 therapy and complement inhibitor-naive pts. In the Phase III APPLY-PNH trial (NCT04558918), iptacopan monotherapy led to clinically meaningful hemoglobin (Hb) increases and normal/near-normal Hb levels in a majority of pts, transfusion avoidance and improved pt-reported fatigue, showing superiority vs C5 inhibitors at Week (Wk) 24. Aim: We report the final APPLY-PNH data after a 24-wk extension period in which all pts received iptacopan monotherapy (study completion: 6 March 2023). Methods: Adult PNH pts (mean Hb &lt;10 g/dL, receiving anti-C5 therapy for ≥6 months) were randomized to receive iptacopan 200 mg twice daily or continue their anti-C5 regimen for 24 wks. Pts could then opt to enter an extension period; pts in the iptacopan arm received iptacopan for another 24 wks and pts who had been receiving anti-C5 switched to iptacopan monotherapy. Results: In the extension period, 95 pts received iptacopan: 61/62 in the iptacopan arm (1 discontinued iptacopan in the randomized period because of pregnancy) and 34/35 in the anti-C5-to-iptacopan arm (1 did not enter the extension period [investigator's decision]). In the iptacopan arm, the improvements at 24 wks were sustained at 48 wks, with maintenance of increased Hb, normal/near-normal mean Hb levels (Figure), improved Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, decreased absolute reticulocyte counts (ARCs) and transfusion avoidance (Table). Pts who switched from anti-C5 to iptacopan had rapid changes in Hb, FACIT-F and ARC, achieving comparable improvements to the iptacopan arm. Mean Hb levels at Wk 48 were 12.2 and 12.1 g/dL in the iptacopan and anti-C5-to-iptacopan arms, respectively (standard deviations 1.6 and 1.4). At Wk 48, the adjusted mean change from baseline in the iptacopan arm was +3.35 g/dL for Hb, +9.80 FACIT-F points and −106.26 × 10 9/L for ARC. In the anti-C5-to-iptacopan arm, the adjusted mean change from baseline at Wk 48 was +3.36 g/dL for Hb, +10.96 FACIT-F points and −107.95 × 10 9/L for ARC (adjusted mean difference in change from baseline at Wk 48 vs Wk 24: +3.02 g/dL, +10.79 points and −102.29 × 10 9/L, respectively). Transfusion avoidance was achieved by 93.5% of pts in the iptacopan arm (Wks 2 to 48) and 94.1% in the anti-C5-to-iptacopan arm (Wks 26 to 48). Mean lactate dehydrogenase levels were generally maintained &lt;1.5 × upper limit of normal in both arms. In the trial, 6/62 pts in the iptacopan arm had clinical breakthrough hemolysis (BTH). One pt in the anti-C5-to-iptacopan arm had clinical BTH after switching to iptacopan. BTH resolved without changing iptacopan dosing. Three pts had major adverse vascular events (MAVEs; randomized period: 1 serious transient ischemic attack [TIA]; extension period: 1 non-serious TIA, 1 serious portal vein thrombosis [PVT]). The pt with PVT had a history of PVT and discontinued heparin prior to the MAVE. All MAVEs were considered unrelated to iptacopan and resolved without changing iptacopan dosing. After 48 wks in the iptacopan arm, the most frequently reported treatment-emergent adverse events (TEAEs) were COVID-19 (29.0% of pts), headache (19.4%), diarrhea (16.1%) and nasopharyngitis (14.5%). There were no deaths, no serious hemolysis TEAEs on iptacopan, no serious infections caused by N. meningitidis, S. pneumoniae or H. influenzae and no pts discontinued treatment because of TEAEs. Conclusions: Long-term data from the Phase III APPLY-PNH trial show a durable response to iptacopan monotherapy in anti-C5-treated PNH pts with persistent anemia. Pts who received iptacopan for 48 wks had sustained improvements in multiple hematological and clinical outcomes, including maintenance of increased Hb, mean normal/near-normal Hb levels, transfusion avoidance and decreased pt-reported fatigue; these benefits quickly emerged in the anti-C5-to-iptacopan arm, supporting the benefit of switching from C5 inhibitors to iptacopan monotherapy. The data indicate good control of hemolysis by iptacopan and a similar safety profile at Wk 48 vs Wk 24. Our findings continue to support oral iptacopan monotherapy as a potentially practice-changing treatment for hemolytic PNH.
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Risitano, Antonio M., Bing Han, Austin Kulasekararaj, et al. "Categorization of Hematological Responses to Oral Iptacopan Monotherapy in Anti-C5-Treated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia in the Phase III APPLY-PNH Trial and Complement Inhibitor-Naïve Patients in the Phase III APPOINT-PNH Trial." Blood 142, Supplement 1 (2023): 4084. http://dx.doi.org/10.1182/blood-2023-180866.
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Background: PNH is an ultrarare disease characterized by complement-mediated hemolysis and consequent anemia. Iptacopan is the first oral, selective complement inhibitor that targets factor B to inhibit the alternative pathway proximally in the complement system. Iptacopan monotherapy led to normal/near normal hemoglobin (Hb) values and transfusion avoidance in the majority of complement inhibitor-naïve patients and anti-C5-treated patients with persistent anemia in the Phase III APPOINT-PNH (NCT04820530) and APPLY-PNH (NCT04558918) trials, respectively, with iptacopan achieving its primary endpoints and demonstrating superiority to anti-C5 treatment in APPLY-PNH. Aim: To apply hematological response categories, adapted from Risitano et al. in Front Immunol 2019, to the data from APPLY-PNH (baseline and Week 24 data) and APPOINT-PNH (Week 24 data). Methods: APPLY-PNH enrolled adult PNH patients with a mean Hb level &lt;10 g/dL who had been receiving eculizumab or ravulizumab for ≥6 months. Patients were randomized 8:5 to receive iptacopan monotherapy 200 mg twice daily or to continue their anti-C5 regimen for 24 weeks. APPOINT-PNH enrolled complement inhibitor-naïve adult PNH patients, with a mean Hb level &lt;10 g/dL and lactate dehydrogenase (LDH) &gt;1.5 × upper limit of normal (ULN); patients received iptacopan monotherapy 200 mg twice daily. Using central laboratory data, hematological responses were categorized primarily based on Hb levels (at baseline and between Days 126 and 168) and the need for packed red blood cell transfusions (in the 6 months prior to baseline and between Days 14 and 168). LDH levels and absolute reticulocyte counts were ancillary indicators to discriminate between complete and major responses. In the original definition of the response categories, absolute reticulocyte count was used to rule out patients with bone marrow failure; however, for this analysis, as patients with laboratory evidence of bone marrow failure were excluded from APPLY-PNH and APPOINT-PNH, absolute reticulocyte count was not used to define the suboptimal categories (ie good, partial, minor and no response categories). Week 24 categories were defined as follows: complete response - median Hb ≥12 g/dL, no transfusions, and both median LDH ≤1.5 × ULN and median absolute reticulocyte count ≤150,000/µL between Days 1 and 168; major response - median Hb ≥12 g/dL, no transfusions, and either LDH &gt;1.5 × ULN or absolute reticulocyte count &gt;150,000/µL between Days 1 and 168; good response - median Hb ≥10 and &lt;12 g/dL and no transfusions; partial response - median Hb ≥8 and &lt;10 g/dL and ≤2 transfusions; minor response - median Hb &lt;8 g/dL and ≤2 transfusions; or median Hb &lt;10 g/dL and 3-6 transfusions; or median Hb &lt;10 g/dL and a reduction in transfusions by ≥50% between Days 14 and 168 compared with the number of transfusions received in the 6 months prior to baseline; no response - median Hb &lt;10 g/dL and &gt;6 transfusions. Results: Sixty-two patients received iptacopan and 35 patients received anti-C5 treatment in the APPLY-PNH trial; 40 patients received iptacopan in the APPOINT-PNH trial. There were no baseline differences between patients in the iptacopan arm and patients in the anti-C5 arm of the APPLY-PNH trial, with most patients having a partial hematological response to complement inhibitor treatment at baseline (62.9% [39/62] of patients in the iptacopan arm and 62.9% [22/35] in the anti-C5 arm; Figure 1). At Week 24, most iptacopan-treated patients in the APPLY-PNH trial achieved a complete response (71% [44/62] of patients versus 0% in the anti-C5 arm; Figure 1). Most patients in the APPOINT-PNH trial also achieved a complete response to iptacopan (62.5% [25/40] of patients; Figure 2). As expected, at Week 24, none of the patients in the anti-C5 arm of APPLY-PNH achieved complete or major hematological responses, with most continuing to maintain a partial hematological response (54.3% [19/35] of patients). Conclusions: This post hoc analysis of the APPLY-PNH and APPOINT-PNH trial data demonstrates that the majority of patients achieved complete or major hematological responses during treatment with iptacopan monotherapy, highlighting the ability of both complement inhibitor-naïve patients and anti-C5-treated patients with persistent anemia to achieve transfusion avoidance and improvement of Hb to normal/near normal levels with iptacopan.
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Panse, Jens Peter, Britta Höchsmann, and Jörg Schubert. "Paroxysmal Nocturnal Hemoglobinuria, Pathophysiology, Diagnostics, and Treatment." Transfusion Medicine and Hemotherapy, August 21, 2024, 310–20. http://dx.doi.org/10.1159/000540474.
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Background: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis (IVH) due to diminished or absent inhibition of the complement system because of deficient expression of cell-anchored complement regulating surface proteins. IVH leads to heterogeneous symptoms such as anemia, abdominal pain, dyspnea, fatigue and increased rates of thrombophilia. Inhibitors of the terminal Complement cascade can reverse IVH leading to a significant reduction of disease burden such as thrombembolic events and also mortality. Summary: Therapeutic inhibitors of the terminal complement cascade such as eculizumab or ravulizumab significantly improve overall survival through IVH-inhibition. However, not all patients experience complete disease control with normalization of hemoglobin levels and absolute reticulocyte counts (ARC) under terminal complement inhibition as a significant part of patients develop extravascular hemolysis (EVH). EVH can be clinically relevant causing persistent anemia and fatigue. New proximal complement inhibitors (CI) mainly targeting complement component C3 or factors of the amplification pathway such as pegcetacoplan, danicopan, and iptacopan became available and are meanwhile approved for marketing. Additional complement-inhibiting strategies are under clinical development. A switch from terminal to proximal CI in patients with significant EVH can achieve hemoglobin and ARC normalization and significant improvement in quality of life (QoL). Additional approvals of proximal CI agents for the treatment of hemolytic PNH in the first line are available for pegcetacoplan and iptacopan. So far, no evidence-based algorithm is available for decision-making in first-line treatment of which type of drug should be used for individual patients. Key Messages: Terminal CIs in hemolytic PNH patients can block IVH and have led to a dramatically improved survival. Proximal CIs ameliorate anemia and improve QoL in patients with relevant EVH. However, more (real-world) data are needed to demonstrate long-term improvement in all patients with hemolytic PNH, especially those under first-line treatment with proximal CI.
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Schmidt, Christoph Q., Britta Höchsmann, and Hubert Schrezenmeier. "The complement model disease paroxysmal nocturnal hemoglobinuria." European Journal of Immunology, August 5, 2024. http://dx.doi.org/10.1002/eji.202350817.
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AbstractWe describe initial, current, and future aspects of complement activation and inhibition in the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare but severe hematological disorder characterized by complement‐mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement‐mediated pathophysiology ultimately led to regulatory approval of the first‐in‐class complement inhibitor, eculizumab, in 2007. This anti‐complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant‐resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti‐C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low‐level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.
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Graf, Michael, and Vincent S. Gallicchio. "History, Etiology, and Treatment of Paroxysmal Nocturnal Hemoglobinuria." Trends in Internal Medicine 2, no. 1 (2022). http://dx.doi.org/10.33425/2771-5906.1015.
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Paroxysmal nocturnal hemoglobinuria is an acquired, rare, nonmalignant hematological disease that is characterized by uncontrolled complement activation and thus intravascular hemolysis. It is caused by somatic mutations in the PIG-A gene that leads to a deficiency in necessary GPI-anchored proteins, which leads to uncontrolled complement activation and thus the clinical manifestations that PNH is often associated with. It is generally accepted that Dr. Paul Strübing first described the disease in 1882, albeit it was Thomas Hale Ham who designed the first diagnostic test (Ham test or acidified serum test) to diagnose the rare disease. Since then, Ham’s test has become obsolete and PNH is detected via flow cytometry. PNH is divided into 3 categories: classical, presence of another bone marrow failure syndrome, and subclinical. Classic PNH is often associated with bone marrow failure, intravascular hemolysis, and/or thrombophilia. A thromboembolic event is the most common cause of mortality for patients with PNH. Before the introduction of anti-complement drugs, allogeneic hematopoietic stem cell transplantation was a common therapy for patients with PNH, although it carried significant risk and has declined drastically as the preferred treatment option of patients. Presently, there are 3 FDA-approved drugs, two terminal complement inhibitors (eculizumab and ravulizumab) and one proximal complement inhibitor (pegcetacoplan). Eculizumab remains the mainstay of treatment as it has since 2007. There is ongoing research and clinical trials in other proximal complement inhibitors to relieve patients of extravascular hemolysis and other common side effects.
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Risitano, Antonio M., Austin G. Kulasekararaj, Jong Wook Lee, et al. "Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria." Haematologica, October 29, 2020, 0. http://dx.doi.org/10.3324/haematol.2020.261826.
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Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p
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Kawahara, Hiroshi, Nobuhide Watanabe, Akihiro Endo, Hiroyuki Yoshitomi, and Kazuaki Tanabe. "Subacute stent thrombosis with spontaneously resolved secondary thrombi in paroxysmal nocturnal hemoglobinuria: a case report." BMC Cardiovascular Disorders 22, no. 1 (2022). http://dx.doi.org/10.1186/s12872-022-02850-z.
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Abstract Background Stent thrombosis (ST) is a serious complication; however, a method to prevent ST in patients with thrombophilic diseases has not been established. Case presentation We report a case of subacute ST in a patient with paroxysmal nocturnal hemoglobinuria (PNH) who was receiving continuous heparin treatment in addition to the usual dual antiplatelet therapy for contrast defects at the proximal site of the occluded right coronary artery and the proximal site of the left circumflex artery. Despite the resolution of thrombi in secondary lesions, subacute ST occurred. After percutaneous coronary intervention for ST, triple therapy, including oral anticoagulation for PNH-related thrombosis, was initiated. The patient subsequently underwent craniotomy hematoma removal for hemorrhagic cerebral infarction. Conclusions Reported cases of ST in patients with PNH are very few, and this case adds evidence with respect to antithrombotic therapy in patients with thrombotic tendencies. Both thrombosis and bleeding should be considered when administering antithrombotic therapy to patients with thrombotic diseases. If there are specific treatments for thrombophilic diseases, they should be initiated early.
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White, Taylor S., Justin R. Arnall, Paul Christopher Parish, Jamie Tolerico, Thuy Tran, and Donald C. Moore. "Proximal complement inhibitors in paroxysmal nocturnal hemoglobinuria: an abundance of options in a rare disease." Expert Review of Hematology, January 6, 2025, 1–5. https://doi.org/10.1080/17474086.2025.2449864.
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Ussowicz, Marek, Dawid Przystupski, Patrycja Mensah-Glanowska, and Agnieszka Piekarska. "Current status and perspectives of hematopoietic cell transplantation in patients with paroxysmal nocturnal hemoglobinuria." Frontiers in Immunology 15 (January 7, 2025). https://doi.org/10.3389/fimmu.2024.1521484.
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BackgroundParoxysmal nocturnal hemoglobinuria (PNH) is a rare complement-driven acquired hemolytic anemia with specific presentations of hemoglobinuria, abdominal pain, fatigue, and thrombosis.ObjectiveTo review the current therapeutic strategies for PNH, including anti-complement therapy and allogeneic hematopoietic cell transplantation (alloHCT), focusing on the tailoring of the approach to the disease subtype.ResultsThe outcome of alloHCT varies depending on disease severity, thrombotic history, and response to prior therapies. Non-transplant PNH therapies include anti-C5 monoclonal antibodies that reduce terminal complement activation (eculizumab, ravulizumab, and crovalimab) and proximal complement pathway inhibitors such as pegcetacoplan (C3 inhibitor), iptacopan (complement factor B inhibitor), and danicopan (complement factor D inhibitor). Although complement inhibitors have revolutionized treatment, alloHCT remains the only curative therapy, particularly for patients who are refractory to medical management or have severe cytopenia. This review outlines the conditioning regimens used in alloHCT and summarizes recent studies showing that overall survival rates improve with less toxic conditioning protocols.ConclusionsAlloHCT can be used to manage PNH, particularly in patients who are resistant to or without access to complement-targeted therapies. Any potential cure offered by alloHCT must be counterbalanced by the significant procedure risks, including graft-versus-host disease and transplant-related mortality, particularly in patients with comorbidities. In the case of severe aplastic anemia with an associated PNH clone, immunoablative protocols based on anti-thymocyte globulin serotherapy with fludarabine and cyclophosphamide are recommended. The use of reduced toxicity protocols with fludarabine has been well-documented in patients with classic PNH. A treosulfan/fludarabine-based regimen is recommended; however, there is no consensus on optimal drug selection.
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Hakimi, Zalmai, Koo Wilson, Eoin McAughey, et al. "The cost–effectiveness, of pegcetacoplan compared with ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria, in a UK setting." Journal of Comparative Effectiveness Research, July 7, 2022, 00. http://dx.doi.org/10.2217/cer-2022-0076.
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Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis. We evaluated, the cost–effectiveness of pegcetacoplan, a novel proximal C3 inhibitor, versus ravulizumab in patients with PNH and hemoglobin levels <10.5 g/dl despite eculizumab treatment in the UK healthcare and social services setting. Materials & methods: A Markov cohort framework model, based on the data from the pivotal trial of pegcetacoplan (PEGASUS/NCT03500549), evaluated lifetime costs and outcomes. Patients transitioned through 3 PNH hemoglobin level/red blood cell transfusion health states. Results: Pegcetacoplan provides lower lifetime costs/greater quality-adjusted life years (£6,409,166/14.694QALYs, respectively) versus ravulizumab (£6,660,676/12.942QALYs). Conclusion: Pegcetacoplan is associated with enhanced anemia control, greater QALYs and reduced healthcare costs versus ravulizumab in the UK healthcare and social services setting.
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Fattizzo, Bruno, Francesco Versino, and Wilma Barcellini. "Breakthrough hemolysis in paroxysmal nocturnal hemoglobinuria throughout clinical trials: from definition to clinical practice." Blood Journal, April 15, 2025. https://doi.org/10.1182/blood.2024027574.
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Breakthrough hemolysis (BTH) is the hemolytic exacerbation occurring in a patient with paroxysmal nocturnal hemoglobinuria (PNH) on treatment with anti-complement therapies. In this review article we analysed the definition, frequency and severity of BTH events across phase 3 clinical trials with terminal (anti-C5 ravulizumab and crovalimab) and complement inhibitors upstream C5 (anti-C3 pegcetacoplan, alternative-pathway inhibitors iptacopan and danicopan), as well as from real-world reports. Furthermore, we reviewed the impact of the various compounds on quality of life and patients reported outcomes. In particular, BTH may occur with all complement inhibitors, with a frequency of 10-15% over 6 months with eculizumab, crovalimab, and pegcetacoplan, and &lt;5% with ravulizumab, iptacopan, and danicopan plus anti-C5. By prolonging the follow-up, the frequency of BTH appeared increased in pegcetacoplan treated patients (nearly 24% at 1 year) as compared to both anti-C5, iptacopan, and double inhibition with danicopan plus anti-C5. BTH risk appears associated with patients' features, particularly suboptimal response/failure of previous complement inhibitor. Transfusions were required in about half of cases and modifications of anti-complement therapy included anticipation of the next anti-C5 dose and addition of eculizumab in patients on proximal inhibitors. Breakthrough thromboses were rare, though anti-coagulant prophylaxis should be considered during severe episodes. Complement amplifying conditions were observed in about half of cases and were more frequently infections. Treatment adherence, optimization of the administration schedule, anticoagulant prophylaxis, as well as education of patients and physicians remain important factors to prevent BTH and its complications.
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Kulesekararaj, Austin, Antonio Maria Risitano, Jaroslaw P. Maciejewski, et al. "Phase 2 Study of Danicopan in Paroxysmal Nocturnal Hemoglobinuria Patients with an Inadequate Response to Eculizumab." Blood, July 27, 2021. http://dx.doi.org/10.1182/blood.2021011388.
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Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral, proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a Phase 2, dose-finding trial, eculizumab-treated, transfusion-dependent PNH patients (n=12) received danicopan 100-200 mg thrice daily in addition to their eculizumab regimen for 24 weeks. Endpoints included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction of blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; one discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean 2.4 g/dL Hgb increase at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared to one transfusion (2 units) in one patient during the 24-week treatment period. Mean FACIT-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to meaningful improvement in Hgb and reduced transfusion requirements in PNH patients who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. Registered at www.clinicaltrials.gov as NCT03472885.
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Kato, Yuta, Mitsuyoshi Hadase, and Takashi Nakamura. "Recurrent acute myocardial and renal infarction with aplastic anemia/paroxysmal nocturnal hemoglobinuria syndrome: A case report." European Heart Journal - Case Reports, September 23, 2024. http://dx.doi.org/10.1093/ehjcr/ytae526.
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Abstract Background Aplastic anemia (AA) is known to progress to paroxysmal nocturnal hemoglobinuria (PNH) during treatment, and thrombosis is a characteristic symptom of PNH. This case report investigates a case of repeated and rapidly progressive multiple arterial thrombosis due to PNH. Case Summary This case is a 24-year-old woman undergoing treatment for AA. She presented with chest pain and underwent emergency coronary angiography. Thrombus occlusion was found in the distal portion of the right coronary artery, acute myocardial infarction was diagnosed and percutaneous coronary intervention was performed. Thrombus aspiration and balloon dilation were performed. Anticoagulants were administered, but chest pain flared up again on Day 9; coronary angiography was performed, indicating that the proximal portion of the right coronary artery had caused occlusion. On Days 9 and 24, she experienced back pain and was diagnosed with renal infarction. Considering that AA had evolved into PNH and intravascular hemolysis and thrombosis appeared, the diagnosis of PNH was made via flow cytometry. Multiple arterial thrombosis due to PNH was diagnosed and ravulizumab treatment was started, resulting in the improvement of thrombus progression, chest pain, and back pain. Discussion Thrombosis due to PNH can recur even after the administration of anticoagulants and antiplatelet agents and has been associated with a high fatality rate. The treatment with ravulizumab, a humanized monoclonal antibody against complement C5, helps with the prevention of thrombosis. Furthermore, anti-complement component C5 therapy is very effective in improving rapidly progressive multiple arterial thrombosis resistant to anticoagulants and antiplatelet agents due to PNH.
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Fishman, Jesse, Koo Wilson, Aleksandra Drzewiecka, Michał Pochopień, and David Dingli. "The cost–effectiveness of pegcetacoplan in complement treatment-naïve adults with paroxysmal nocturnal hemoglobinuria in the USA." Journal of Comparative Effectiveness Research, August 31, 2023. http://dx.doi.org/10.57264/cer-2023-0055.
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Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis, and is associated with high healthcare burden. We evaluated the cost–effectiveness of pegcetacoplan, a proximal complement-3 inhibitor (C3i), compared with the C5i, eculizumab and ravulizumab, in complement treatment-naive adults with PNH, from the US healthcare payer perspective. Materials & methods: A de novo cost–effectiveness model based on a Markov cohort structure evaluated lifetime (55-year) PNH costs and outcomes. The 6-month cycles of the model reflected the follow-up period of PRINCE (NCT04085601), an open-label trial of pegcetacoplan compared with eculizumab in C5i-naive patients. Data from PRINCE informed the clinical, safety and health-related quality of life outcomes in the model. Results: Pegcetacoplan was associated with lifetime cost savings of USD1,176,808 and USD213,062 relative to eculizumab and ravulizumab, respectively (largely attributed to reduced drug costs and blood transfusions), and additional quality-adjusted life years (QALYs) of 0.25 and 0.24. Conclusion: In patients with PNH who are treatment-naive, the base-case cost–effectiveness analysis, scenario analysis and sensitivity analysis showed both lifetime cost savings and increased QALYs associated with pegcetacoplan compared with eculizumab or ravulizumab in the USA.
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Füreder, Wolfgang, Renate Thalhammer, and Peter Valent. "Resolution of extravascular hemolysis with oral iptacopan monotherapy in a patient with treatment experienced paroxysmal nocturnal hemoglobinuria (PNH)." Wiener klinische Wochenschrift, July 1, 2024. http://dx.doi.org/10.1007/s00508-024-02390-w.
Full textAbstract:
SummaryParoxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder characterized by a loss of glycosyl-phosphatidyl-inositol-linked (GPI) proteins on various hematopoietic cells. Some GPI proteins are involved in the regulation of the complement system, and their absence renders erythrocytes susceptible to complement-mediated lysis. Current standard of care in PNH is to block the complement system at the level of C5 using ravulizumab or eculizumab; however, some patients with PNH may develop extravascular hemolysis (EVH) during treatment with C5 inhibitors. The proximal complement inhibitor iptacopan has recently been shown to be efficacious in patients with PNH. This article reports on a 43-year-old female patient with PNH who was successfully treated with iptacopan. The patient had received ravulizumab for several years and developed a clinically relevant EVH. After obtaining informed consent, the patient received oral iptacopan 200 mg twice daily and ravulizumab was discontinued. Over the next few weeks hemoglobin levels and reticulocyte counts normalized. The patient reported mild flushes with erythema, chills, and mild muscle pain, all of which resolved during follow-up. No breakthrough hemolysis occurred, and no severe adverse events were recorded.
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Risitano, Antonio M., Serena Marotta, Patrizia Ricci, et al. "Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT." Frontiers in Immunology 10 (June 14, 2019). http://dx.doi.org/10.3389/fimmu.2019.01157.
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Kulasekararaj, Austin G., David J. Kuter, Morag Griffin, Ilene C. Weitz, and Alexander Röth. "Biomarkers and laboratory assessments for monitoring the treatment of patients with paroxysmal nocturnal hemoglobinuria: Differences between terminal and proximal complement inhibition." Blood Reviews, January 2023, 101041. http://dx.doi.org/10.1016/j.blre.2023.101041.
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