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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]

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]

Neurological disorders usually present very heterogeneous recovery patterns. Nonetheless, accurate prediction of future clinical end-points and robust definition of homogeneous cohorts are necessary for scientific investigation and targeted care. For this, unbiased recursive partitioning with conditional inference trees (URP-CTREE) have received increasing attention in medical research, especially, but not limited to traumatic spinal cord injuries (SCIs). URP-CTREE was introduced to SCI as a clinical guidance tool to explore and define homogeneous outcome groups by clinical means, while providing high accuracy in predicting future clinical outcomes. The validity and predictive value of URP-CTREE to provide improvements compared with other more common approaches applied by clinicians has recently come under critical scrutiny. Therefore, a comprehensive simulation study based on traumatic, cervical complete spinal cord injuries provides a framework to investigate and quantify the issues raised. First, we assessed the replicability and robustness of URP-CTREE to identify homogeneous subgroups. Second, we implemented a prediction performance comparison of URP-CTREE with traditional statistical techniques, such as linear or logistic regression, and a novel machine learning method. URP-CTREE's ability to identify homogeneous subgroups proved to be replicable and robust. In terms of prediction, URP-CTREE yielded a high prognostic performance comparable to a machine learning algorithm. The simulation study provides strong evidence for the robustness of URP-CTREE, which is achieved without compromising prediction accuracy. The slightly lower prediction performance is offset by URP-CTREE's straightforward interpretation and application in clinical settings based on simple, data-driven decision rules. [ABSTRACT FROM AUTHOR]

We study and compare several variants of random forests tailored to prognostic models for ordinal outcomes. Models of the conditional odds function are employed to understand the various random forest flavours. Existing random forest variants for ordinal outcomes, such as Ordinal Forests and Conditional Inference Forests, are evaluated in the presence of a non-proportional odds impact of prognostic variables. We propose two novel random forest variants in the model-based transformation forest family, only one of which explicitly assumes proportional odds. These two novel transformation forests differ in the specification of the split procedures for the underlying ordinal trees. One of these split criteria is able to detect changes in non-proportional odds situations and the other one focuses on finding proportional-odds signals. We empirically evaluate the performance of the existing and proposed methods using a simulation study and illustrate the practical aspects of the procedures by a re-analysis of the respiratory sub-item in functional rating scales of patients suffering from Amyotrophic Lateral Sclerosis (ALS). [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions To evaluate the tolerability of crovalimab versus eculizumab in C5 inhibitor (C5i)‐naive and ‐experienced patients with PNH from COMMODORE 2, 3 and 1 (NCT04434092, NCT04654468 and NCT04432584).Pooled safety data were assessed in the total crovalimab and eculizumab populations and by C5i‐naive versus C5i‐switched status in patients receiving crovalimab. Analyses include 6.5 months of additional follow‐up from the COMMODORE 2 and 1 primary analyses.COMMODORE safety data (crovalimab, 393 patients [naive, 192 patients; switched, 201 patients]; eculizumab, 111 patients) were analysed. The total patient years (PY) were 503.9 and 51.1 in the total crovalimab and eculizumab populations, respectively, with 471 and 581 adverse events (AEs) per 100 PY. Serious infection rates were 8.9 and 13.7 AEs per 100 PY, respectively; no meningococcal infections were reported. Fatal AEs occurred in eight (2%) patients receiving crovalimab (naive, six patients; switched, two patients) and one (1%) receiving eculizumab, all treatment unrelated. In C5i‐switched patients, 39 (19%) had transient immune complex reactions (risk when switching between C5i and crovalimab); the majority were Grades 1–2 arthralgia and rash, and 16 (8%) had Grade 3 events.Crovalimab's safety profile was consistent with eculizumab's and was generally comparable between C5i‐naive and C5i‐switched patients. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the tolerability of crovalimab versus eculizumab in C5 inhibitor (C5i)-naive and -experienced patients with PNH from COMMODORE 2, 3 and 1 (NCT04434092, NCT04654468 and NCT04432584)., Methods: Pooled safety data were assessed in the total crovalimab and eculizumab populations and by C5i-naive versus C5i-switched status in patients receiving crovalimab. Analyses include 6.5 months of additional follow-up from the COMMODORE 2 and 1 primary analyses., Results: COMMODORE safety data (crovalimab, 393 patients [naive, 192 patients; switched, 201 patients]; eculizumab, 111 patients) were analysed. The total patient years (PY) were 503.9 and 51.1 in the total crovalimab and eculizumab populations, respectively, with 471 and 581 adverse events (AEs) per 100 PY. Serious infection rates were 8.9 and 13.7 AEs per 100 PY, respectively; no meningococcal infections were reported. Fatal AEs occurred in eight (2%) patients receiving crovalimab (naive, six patients; switched, two patients) and one (1%) receiving eculizumab, all treatment unrelated. In C5i-switched patients, 39 (19%) had transient immune complex reactions (risk when switching between C5i and crovalimab); the majority were Grades 1-2 arthralgia and rash, and 16 (8%) had Grade 3 events., Conclusions: Crovalimab's safety profile was consistent with eculizumab's and was generally comparable between C5i-naive and C5i-switched patients., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)