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Objectives: To describe real‐world use/effectiveness of pegcetacoplan (PEG) in paroxysmal nocturnal haemoglobinuria (PNH). Methods: Data were drawn from the Adelphi PNH Disease Specific Programme™, a cross‐sectional survey conducted in France, Italy, Germany, Spain and the United States from January to November 2022. Patients had a confirmed PNH diagnosis and received PEG for ≥1 month. Physicians reported patient characteristics, treatment use/satisfaction and their perception of patients' fatigue and health‐related quality of life (HRQoL). Patients reported treatment satisfaction and completed questionnaires assessing fatigue, HRQoL and productivity. Descriptive statistics were reported. Results: Overall, 14 physicians provided data for 61 patients who had received 1080 mg/dose PEG for 1.3–14.8 months. At data collection compared to PEG initiation: haemoglobin was 2.5 g/dL higher on average; proportion of patients with lactate dehydrogenase (LDH) ≥1.5 × upper limit of normal was reduced by 27.4%; physician‐perceived fatigue was lower and HRQoL better. Physician‐ and patient‐reported treatment satisfaction was high for >90% of patients. Physicians and patients were more satisfied with PEG than previously prescribed C5 complement inhibitors. Mean work impairment and activity impairment in the 7 days prior to data collection were 32.9% and 22.4%, respectively. Conclusions: These real‐world data support the effectiveness of PEG through positive effects on haemoglobin, LDH, fatigue and HRQoL. [ABSTRACT FROM AUTHOR]

Objectives: Data from the International PNH Registry (NCT01374360) were used to estimate the overall survival and first occurrence of thromboembolic events/major adverse vascular events (TEs/MAVEs) for eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) compared with a contemporaneous untreated cohort. Methods: Patients enrolled in the Registry from March 16, 2007, to February 14, 2022, were included. Treated patients received eculizumab for >35 days; untreated patients did not receive eculizumab at any time. Univariable and multivariable analyses were performed using a Cox proportional hazards regression model comparing eculizumab treatment periods to untreated periods and were adjusted for baseline covariates (e.g., high disease activity [HDA], transfusion dependency, and eculizumab treatment status). Results: The analysis included 4118 patients. The univariable hazard ratio (HR) (95% CI) for mortality in eculizumab-treated time versus untreated time was 0.51 (0.41-0.64; p < 0.0001). Significant baseline covariates included age, sex, history of bone marrow failure, ≥4 erythrocyte transfusions within 12 months before baseline, and an estimated glomerular filtration rate = 60 mL/min/1.73 m² (all p < 0.0001). In the adjusted analysis, patients with baseline HDA had the greatest reduction in mortality risk (HR [95% CI], 0.51 [0.36-0.72]). Treated patients had approximately 60% reduction in TE/MAVE risk during treated versus untreated time (HR [95% CI]: TE: 0.40 [0.26-0.62], MAVE: 0.37 [0.26-0.54]; p < 0.0001). Conclusion: Using data from the largest Registry of patients with PNH, with ≥14 years of overall follow-up, we demonstrate that treatment with eculizumab conferred a 49% relative benefit in survival and an approximately 60% reduction in TE/MAVE risk. [ABSTRACT FROM AUTHOR]

Objectives: This study reports long‐term outcomes from the open‐label extension (OLE) period of the Phase I/II COMPOSER trial (NCT03157635) that evaluated crovalimab in patients with paroxysmal nocturnal haemoglobinuria, who were treatment‐naive or switched from eculizumab at enrolment. Methods: COMPOSER consists of four sequential parts followed by the OLE. The primary OLE objective was to assess long‐term crovalimab safety, with a secondary objective to assess crovalimab pharmacokinetics and pharmacodynamics. Exploratory efficacy endpoints included change in lactate dehydrogenase (LDH), transfusion avoidance, haemoglobin stabilisation and breakthrough haemolysis (BTH). Results: A total 43 of 44 patients entered the OLE after completing the primary treatment period. Overall, 14 of 44 (32%) experienced treatment‐related adverse events. Steady state exposure levels of crovalimab and terminal complement inhibition were maintained over the OLE. During the OLE, mean normalised LDH was generally maintained at ≤1.5× upper limit of normal, transfusion avoidance was achieved in 83%–92% of patients and haemoglobin stabilisation was reached in 79%–88% of patients across each 24‐week interval. Five BTH events occurred with none leading to withdrawal. Conclusions: Over a 3‐year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved. Intravascular haemolysis control, haemoglobin stabilisation and transfusion avoidance were maintained, signifying long‐term crovalimab efficacy. [ABSTRACT FROM AUTHOR]

Objective: Describe the real‐world clinical profile of eculizumab‐treated patients by characterizing their short‐ and long‐term clinical and laboratory outcomes. Methods: This retrospective study used preexisting medical records of eculizumab‐treated patients with paroxysmal nocturnal hemoglobinuria (PNH) at the University Hospital Essen. Hematologic response, breakthrough hemolysis, transfusion dependence, and other outcomes were assessed. Results: Of 85 patients with PNH, 76 received eculizumab for ≥24 weeks (mean follow‐up: 5.59 years; total: 425 person‐years). At 24 weeks (n = 57 patients with data), 7% and 9% had complete and major hematologic response, respectively. Breakthrough hemolysis occurred in 8%, and 38% required a blood transfusion. Over long‐term follow‐up (25–264 weeks), 70%–82% of patients did not achieve complete or major hematologic response in any 24‐week period. Breakthrough symptoms, breakthrough hemolysis, and transfusion dependence occurred in 63%, 43%, and 63% of patients, respectively, at any point during follow‐up. The majority (79%–89%) of patients did not achieve normalized hemoglobin, with 76%–93% having elevated bilirubin or absolute reticulocyte count in any 24‐week window. Mean percentage reduction in lactate dehydrogenase (baseline to end of follow‐up) was 80.3% (95% CI, 64.0–96.6). Conclusions: A considerable proportion of patients with PNH receiving eculizumab did not achieve optimal clinical outcomes and had an ongoing disease burden. [ABSTRACT FROM AUTHOR]

Drug–target–drug complexes (DTDCs) are phenomena newly observed in patients who switch from the complement component 5 (C5) inhibitor eculizumab to crovalimab, a novel, anti‐C5 antibody in development for paroxysmal nocturnal hemoglobinuria (PNH), because these agents bind to different C5 epitopes. In Part 3 of the four‐part, phase I/II COMPOSER study, 19 patients with PNH switching from eculizumab received 1,000‐mg crovalimab intravenously, then subcutaneous maintenance doses from Day 8 (680 mg every 4 weeks (q4w), 340 mg every 2 weeks, or 170 mg every week). Crovalimab exposure was transiently reduced, and size‐exclusion chromatography and crovalimab‐specific enzyme‐linked immunosorbent assays revealed DTDCs in all 19 patients' sera. Additionally, self‐limiting mild to moderate symptoms suggestive of type III hypersensitivity reactions occurred in two patients. Mathematical modeling simulations of DTDC kinetics and effects of dosing on DTDC size distribution using Part 3 data predicted that increased crovalimab concentrations could reduce the proportion of large, slow‐clearing DTDCs in the blood. A simulation‐guided, optimized crovalimab regimen (1,000 mg intravenously; four weekly, subcutaneous 340‐mg doses; then 680 mg q4w from Day 29) was evaluated in Part 4. Confirming the model's predictions, mean proportions of large DTDCs in patients who switched from eculizumab to this optimized regimen decreased by > 50% by Day 22, and target crovalimab concentrations were maintained. No type III hypersensitivity reactions occurred in Part 4. Optimizing crovalimab dosing thus reduced the proportion of large DTDCs, ensured adequate complement inhibition, and may improve safety. Model‐based dosing optimization to mitigate DTDC formation offers a useful strategy for patients switching to novel antibody treatments targeting soluble epitopes. [ABSTRACT FROM AUTHOR]

Cold agglutinin disease (CAD) is a rare chronic autoimmune haemolytic anaemia, driven mainly by classical complement pathway activation, leading to profound fatigue and poor quality of life. In the Phase 3 CADENZA trial, sutimlimab—a C1s complement inhibitor—rapidly halted haemolysis, increased haemoglobin levels and improved fatigue versus placebo in patients with CAD without a recent history of transfusion. Patient‐reported outcomes (PROs) included Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐Fatigue), 12‐Item Short Form Health Survey (SF‐12), EuroQol visual analogue scale (EQ‐VAS), Patient Global Impression of Change (PGIC) and Patient Global Impression of (fatigue) Severity (PGIS). Sutimlimab resulted in significant rapid and meaningful improvements versus placebo in PROs. From Week 1, the FACIT‐Fatigue mean score increased >5 points above baseline (considered a clinically important change [CIC]). Least‐squares (LS) mean change in FACIT‐Fatigue score from baseline to treatment assessment timepoint was 10.8 vs. 1.9 points (sutimlimab vs. placebo; p < 0.001). Improvements in physical (PCS) and mental (MCS) component scores of the SF‐12 were also considered CICs (LS mean changes from baseline to Week 26: PCS 5.54 vs. 1.57 [p = 0.064]; MCS 5.65 vs. –0.48 [p = 0.065]). These findings demonstrate that in addition to improving haematologic parameters, sutimlimab treatment demonstrates significant patient‐reported benefits. Study registered at www.clinicaltrials.gov: NCT03347422. [ABSTRACT FROM AUTHOR]

Paravertebral extramedullary hematopoietic masses (EHMs) account for up to 15% of extramedullary pseudotumors in beta‐thalassemia (BT) and are most likely related to compensatory hematopoiesis. In most cases, pseudotumors are incidentally detected, as the majority of patients are asymptomatic. Since June 2020, luspatercept is approved for the treatment of patients with BT who require regular red blood cell transfusions. Data addressing the safety and efficacy of luspatercept in patients with BT‐associated EHMs are pending. To date (May 2022), paravertebral EHMs were observed in two asymptomatic patients out of currently 43 adult patients with BT registered at the Adult Hemoglobinopathy Outpatient Unit of the University Hospital Essen, Germany. In one of them, a paravertebral EHM was diagnosed more than 10 years prior to referral. Throughout observation time, treatment with luspatercept was associated with a clinically significant reduction in transfusion burden while allowing to maintain a baseline hemoglobin concentration of ≥10 g/dL aiming to suppress endogenous (ineffective) erythropoiesis associated with BT. Considering the rarity of paravertebral EHMs in BT, luspatercept might potentially represent a novel therapeutic option for these often‐serious disease‐associated complications. However, appropriate follow‐up investigations are recommended to detect (early) treatment failures secondary to an undesired luspatercept‐associated erythroid expansion. [ABSTRACT FROM AUTHOR]

COVID‐19 is a potential life‐threatening viral disease caused by SARS‐CoV‐2 and was declared a pandemic by the WHO in March 2020. mRNA‐based SARS‐CoV‐2 vaccines are routinely recommended in immune‐compromised patients, including patients with AA, as these patients are at increased risk of contracting COVID‐19 and developing a more severe course of disease. Between March 2021 and November 2021 relapse of AA occurred in four (age [median]: 53 years, range 30–84 years) out of 135 patients currently registered at our department and two de novo cases of AA in temporal context to vaccination against SARS‐CoV‐2, were documented. Median time after first COVID‐19 vaccination and relapse of AA was 77 days. All relapsed patients were vaccinated with the mRNA‐based vaccine Comirnaty®. Relapse in two out of the four patients was refractory to CsA/eltrombopag, favoring IST with hATG/CsA or BMT, respectively. Our observations should prompt clinicians to take vaccine‐induced relapse of AA or de novo AA after SARS‐CoV‐2 vaccination into account. Furthermore, careful clinical monitoring and vigilance for signs or symptoms that may indicate relapse of AA (e.g., bleeding complications) are indicated. [ABSTRACT FROM AUTHOR]

One patient had two SAEs (bile duct stone and cholelithiasis) that were not treatment related, and the other had a treatment-related SAE (upper respiratory tract infection) that resolved while on treatment. Keywords: anti-C5 inhibitor; C5 polymorphism; COMPOSER; crovalimab; paroxysmal nocturnal haemoglobinuria EN anti-C5 inhibitor C5 polymorphism COMPOSER crovalimab paroxysmal nocturnal haemoglobinuria e46 e50 5 07/27/22 20220801 NES 220801 Paroxysmal nocturnal haemoglobinuria (PNH) is characterised by the loss of complement regulators CD55 and CD59 on peripheral blood elements, which can result in intravascular haemolysis and thrombosis.1 C3 (pegcetacoplan) and C5 (eculizumab and ravulizumab) inhibitors are approved therapies for PNH and can control intravascular haemolysis in patients with PNH.2-5 However, eculizumab and ravulizumab lack efficacy in patients with inherited nonsynonymous polymorphisms in the C5 subunit (i.e. c.2654G -> A and c.2653C -> T) affecting Arg885, which corresponds to their target epitope.5,6 Such polymorphisms are present in <=3.5% of individuals of Asian descent and have been reported in a patient with no known Asian ancestry.5-8 Hence, patients with PNH and C5 polymorphism have a high unmet clinical need.5,6 The newly approved C3 inhibitor pegcetacoplan, which blocks the complement cascade upstream of C5, may be effective in treating these patients, but specific data are unavailable.2 Therefore, these patients should be enrolled in an appropriate study. Overall, the response to previous therapy in these patients with C5 SNP was consistent with the typical poor haemolysis control experienced with eculizumab or ravulizumab in such patients.5,6 With crovalimab treatment, all four patients achieved sustained terminal complement inhibition and haemolysis control consistent with all patients in COMPOSER.10 Three serious adverse events (SAEs) were reported in two patients. [Extracted from the article]