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Abstract: Immunosuppressive therapy using horse antithymocyte globulin (ATG; h-ATG) combined with cyclosporine (CsA) and eltrombopag is the standard care for aplastic anemia (AA) in patients without a suitable matched donor. However, in many countries, h-ATG use has been discontinued, leaving rabbit ATG (r-ATG), which has a lower response rates and poorer survival, as the only alternative. In previous studies, alemtuzumab (ALZ), a humanized monoclonal antibody targeting CD52, combined with CsA, resulted in an adequate overall response rate (ORR) in patients with AA. This study describes a multicenter, international retrospective analysis of ALZ for treating AA.We analyzed a series of patients who received subcutaneous ALZ for AA in 4 centers in Brazil and the United Kingdom from March 2009 to January 2024. We analyzed 64 ALZ treatments in 61 adult patients with AA, 76% with severe AA (SAA) or very SAA. The ORR was 59.4% at 12 months (complete, 21.9%; partial, 37.5%). Cumulative incidence (CI) of response was 54.7% at 6 months and 59.4% at 12 months. Younger patients (age <65 years) had higher CI of response (67% vs 31%; P = .03), as did patients treated with a total dose of 103 mg (70% vs 38%; P = .02). Overall survival was 86% at 1 year, 78% at 2 years, and 70% at 4 years, significantly higher in responders (90% vs 44%; P < .0001). Adverse events were of low grade, and infectious events were infrequent. Subcutaneous ALZ is a feasible, effective, and safe alternative to r-ATG for patients with AA requiring immunosuppressive treatment when h-ATG access is limited., (© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Light chain amyloidosis and transthyretin amyloidosis are rare protein misfolding disorders characterized by amyloid deposition in organs, varied clinical manifestations, and poor outcomes. Amyloid fibrils trigger various signaling pathways that initiate cellular, metabolic, structural, and functional changes in the heart and other organs. Imaging modalities have advanced to enable detection of amyloid deposits in involved organs and to assess organ dysfunction, disease stage, prognosis, and treatment response. The Amyloidosis Forum hosted a hybrid meeting to focus on the use of imaging endpoints in clinical trials for systemic immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Stakeholders from academia and industry, together with representatives from multiple regulatory agencies reviewed the use of imaging biomarkers with a focus on cardiac amyloidosis, described applications and limitations of imaging in clinical trials, and discussed qualification of imaging as a surrogate clinical outcome. Survey results provided important patient perspectives. This review summarizes the proceedings of the Amyloidosis Forum., Competing Interests: Funding Support and Author Disclosures The Amyloidosis Forum is funded by the Amyloidosis Research Consortium (ARC). ARC is funded through private/philanthropic donations and grants from for-profit pharmaceutical and biotechnology companies. ARC retains all influence, control, and autonomy over projects for which it has received external support. ARC has received grants from Alexion, Alnylam, Attralus, joint funding from AstraZeneca and Ionis, BridgeBio, GlaxoSmithKline, Intellia Therapeutics, Janssen, Life Molecular Imaging, Pfizer, Protego, and Prothena in support of the Amyloidosis Forum Pathways for the Development of Imaging Endpoints meeting. ARC was responsible for designing the meeting, co-developing the meeting agenda, recruitment of speakers, moderators, and panelists, production of meeting materials, hosting the hybrid meeting, and publications. U.S. Government Employee Disclaimer: This paper reflects the views of the authors and should not be construed to represent official views or policies of the U.S. Food and Drug Administration, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), or the U.S. Department of Health and Human Services. Medicines and Healthcare Products Regulatory Agency (MHRA) Disclosure: The positions expressed in this document are individual opinions and should not be interpreted as agreed positions or policy of MHRA or the UK government. European Medicines Agency (EMA) Disclosure: This paper reflects the views of the authors and should not be interpreted as official positions of EMA, or member agencies, specifically the Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM), or Agence Nationale de Securite du Medicament et des Produtis de Sante (ANSM). Dr Dorbala has received research grants from Pfizer, Attralus, GE Healthcare, Siemens, and Phillips; and consulting fees from Pfizer, BridgeBio, Novo Nordisk, and MedScape. Dr Alexander has received consulting fees from Alnylam, Arbor Biotechnologies, Bristol Myers Squibb, Intellia, and Novo Nordisk. Dr Brambatti is a shareholder at Ionis pharmaceuticals and employee and shareholder at Merck and Co. Dr Cuddy has received grant support from NIH 1K23HL166686-01 and American Heart Association 23CDA857664; and personal fees from Pfizer, Eidos/BridgeBio, Ionis, AstraZeneca, and Novo Nordisk. Dr Dispenzieri is on the advisory board and independent review committee of Janssen, Oncopeptides, and Sorrento; is on the data monitoring safety committee of Alnylam, Pfizer, and Takeda; and has received research dollars from BMS. Dr Ezzeddine has received research grants from Pfizer Inc; consulting fees from Alnylam Pharmaceuticals and Medscape from WebMD; and intellectual property on AI-enabled amyloid detection from ECG/Anumana, Inc. Dr Falk has received consulting fees from Alnylam and AstraZeneca. Dr Fontana is on the advisory board and/or a consultant for Alexion, Alnylam, Caelum, Intellia, Janssen, Novo Nordisk, Pfizer, Attralus, Lexeo, and Prothena. Dr Grodin has received sources of funding from Texas Health Resources Clinical Scholarship, Pfizer, Eidos/BridgeBio, and NHLBI (R01HL160892); and consultancy fees from Alnylam, AstraZeneca, Intellia Pfizer, Eidos/BridgeBio, and Sarepta. Dr Guthrie is an employee and shareholder of Attralus. Dr Hofling is a U.S. government employee. Dr Lin is an advisory board member for Ionis (Cardio TTransform Trial); and has received research funding for an investigator-initiated trial on TTR amyloid from Pfizer and Biotronik. Dr Masri has received research grants from Pfizer, Ionis, Attralus, and Cytokinetics; and fees from Cytokinetics, BMS, Eidos, Pfizer, Ionis, Lexicon, Alnylam, Attralus, Haya, BioMarin, and Tenaya. Dr Maurer has received grant support from NIH R01HL139671 and R01AG081582-01; grants and personal fees from Alnylam, Pfizer, Eidos, Prothena, and Ionis; and personal fees from AstraZeneca, Akcea, Intellia, and Novo Nordisk. Dr Mittmann is an employee of EMA/BrArM. Dr Quarta is an Alexion/AstraZeneca employee. Dr Race is an employee of EMA/ANSM. Dr Rajendran is a U.S. government employee. Dr Ruberg has received research grants from NIH/NHLBI (HL139671), Alnylam, Akcea/Ionis, and Pfizer; and consulting fees from AstraZeneca. Dr Sanchorawala has received research support from Celgene, Millennium-Takeda, Janssen, Prothena, Sorrento, Karyopharm, Oncopeptide, Caelum, and Alexion; consultant fees from Pfizer, Jansen, and Attralus; and is on the scientific advisory board for Proclara, Caelum, Abbvie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena, and AstraZeneca. Dr Signorovitch is an employee of Analysis Group, Inc, which has received consulting fees from ARC. Dr Sirac has received a research grant from Attralus, Inc. Dr Soman has received institutional grants from Pfizer; and consultancy fees from Pfizer, Anylam, BridgeBio, and Spectrum Dynamics. Dr Sperry has received personal fees from Pfizer, AstraZeneca, Alnylam, and BridgeBio. Dr Stephens is a full-time employee of Life Molecular Imaging, GmbH. Dr Stockbridge is a U.S. government employee. Dr Vest is an employee and shareholder of Alnylam Pharmaceuticals. Dr Wall is an inventor of IP related to iodine (124)I evuzamitide; and is co-founder, shareholder, and chief scientific officer of Attralus, Inc. Dr Wechalekar is on the advisory board/received honorarium from Janssen, GlaxoSmithKline, Prothena, Alexion/AstraZeneca, and Attralus. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Solid-state protein formulations are known to exhibit enhanced storage stability compared to their liquid dosage form counterparts. pH is one of the factors affecting the stability of protein formulations. The pH of protein formulations in the solution could be influenced by the buffer used, directly impacting their solid-state stability. During lyophilization, buffer components may interact with other formulation components present in the protein formulations, causing a pH shift. This study aimed to investigate the effects of phosphate buffer and amino acid buffers (such as histidine and/or arginine) on the physical properties and accelerated storage stability of spray freeze-dried or lyophilized protein formulations. A model protein, bovine serum albumin (BSA), was used to prepare high-concentration protein formulations. The formulations consisted of BSA, trehalose, and mannitol in an 80:15:5 ratio (w/w), respectively. Various buffers were utilized in the preparation of protein formulations, and the resultant solid formulations underwent screening via accelerated stability study using size exclusion chromatography (SEC). The combination of phosphate and arginine buffers resulted in increased monomer loss in the accelerated storage stability study. Additional characterizations, including solid-state Fourier transform infrared spectroscopy (ssFTIR) and powder X-ray diffraction (PXRD), were conducted. While these analyses did not definitively elucidate the mechanism behind the observed instability, their outcomes provide valuable insights for further investigation, highlighting the need for future research in this area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Individualized treatment rules inform tailored treatment decisions based on the patient's information, where the goal is to optimize clinical benefit for the population. When the clinical outcome of interest is survival time, most of current approaches typically aim to maximize the expected time of survival. We propose a new criterion for constructing Individualized treatment rules that optimize the clinical benefit with survival outcomes, termed as the adjusted probability of a longer survival. This objective captures the likelihood of living longer with being on treatment, compared to the alternative, which provides an alternative and often straightforward interpretation to communicate with clinicians and patients. We view it as an alternative to the survival analysis standard of the hazard ratio and the increasingly used restricted mean survival time. We develop a new method to construct the optimal Individualized treatment rule by maximizing a nonparametric estimator of the adjusted probability of a longer survival for a decision rule. Simulation studies demonstrate the reliability of the proposed method across a range of different scenarios. We further perform data analysis using data collected from a randomized Phase III clinical trial (SWOG S0819)., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic blood disorder. Symptoms such as fatigue can have a substantial impact on patients' physical activity levels, sleep, quality of life, and work productivity. Ravulizumab treatment can reduce thrombosis risk, improve survival and quality of life, and reduce fatigue in PNH, but information is limited on how it impacts sleep and physical activity. Here, data on resting heart rate, daily physical activity, and sleep in ravulizumab-treated patients with PNH were passively collected via a digital wearable activity-tracking device and patient-reported outcome (PRO) data were collected via weekly surveys in the same cohort., Methods: REVEAL was a 32-week prospective observational cohort study in individuals with PNH receiving ravulizumab in the USA. A wrist-worn Fitbit™ collected data on resting heart rate, daily step count, and sleep duration from eligible patients. Patients also completed the following electronic weekly surveys: Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue, Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health, PROMIS Global Mental Health, PROMIS Sleep-Related Impairment and Sleep Disturbance, and Work Productivity and Activity Impairment Questionnaire - Specific Health Problem (WPAI-SHP). Data collected from the activity trackers and surveys were compared against US general population values reported in the literature., Results: Twenty-eight ravulizumab-treated patients were included (median age: 34 years; 54% female). PRO scores were within US general population normative values, including FACIT-Fatigue (40.0), PROMIS Global Physical Health (51.0), Global Mental Health (51.0), Sleep-Related Impairment (50.0), and Sleep Disturbance (49.0). Similarly, mean resting heart rate (67 bpm), daily step count (7476), and sleep duration (7.7 h) were within the range of US general population values. Daily step count was positively correlated with PROMIS Global Physical and Mental Health scores., Conclusions: This was the first study to use digital monitoring technology to collect data on physical activity and sleep in patients with PNH. The findings indicate that ravulizumab treatment enables patients with PNH to achieve activity levels (heart rate, sleep duration, step count) and quality of life that are comparable to those of the US general population. A weak positive correlation was identified between patient-reported physical and mental health and daily physical activity levels., (© 2024. The Author(s).)

Objective: To evaluate the safety and efficacy of BI 1467335 in patients with non-proliferative diabetic retinopathy (NPDR)., Methods: ROBIN is a Phase IIa, double-masked, randomised, placebo-controlled study (NCT03238963). Patients with NPDR and without centre-involved diabetic macular oedema were included; all had a best corrected visual acuity letter score of ≥70 Early Treatment Diabetic Retinopathy Study letters in the study eye at screening. Patients received oral BI 1467335 10 mg or placebo once daily for 12 weeks. Post-treatment follow-up was 12 weeks. The primary endpoint was the proportion of patients over the 24 weeks with ocular adverse events (AEs). Secondary endpoints were the proportion of patients with ≥2-step improvement from baseline in DRSS severity level at Week 12 and the proportion of patients with non-ocular AEs at 24 weeks., Results: Seventy-nine patients entered the study (BI 1467335, n = 40; placebo, n = 39). The proportion of patients with ocular AEs over 24 weeks was greater in the BI 1467335 versus the placebo group (35.0% vs 23.1%, respectively). Treatment-related AEs were reported for similar numbers of patients in the placebo and BI 1467335 group (7.7% vs 7.5%, respectively). At Week 12, 5.7% (n = 2) of patients in the BI 1467335 group had a 2-step improvement in DRSS severity level from baseline, compared with 0% in the placebo group., Conclusions: BI 1467335 was well tolerated by patients with NPDR. There was a high variability in DRSS levels for individual patients over time, with no clear efficacy signal., (© 2024. The Author(s).)

Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research., Competing Interests: Disclosures Silvia Zaragoza Domingo Developed EPICOG-SCH Brief Cognitive Battery in Schizophrenia and provided services as consultant to pharma industry (Sanofi-Genzyme and Jazz Pharmaceuticals in different periods 2018-23). Jordi Alonso, Montserrat Ferrer, Peter Annas, Chris Edgar, Manuel de Gracia, Georg Dorffner, Brian Harel, Jan Kottner, Amy Pinkham and Daniella Tinoco, Maria T. Acosta, Larry Alphs, John Harrison and Judith Jaeger have no conflicts of interest. For Florence Butlen-Ducuing and Pavel Balabanov, the views expressed in this document are the personal views of the authors and may not be understood or quoted as being made for or reflecting the position of the European Medicines Agency (EMA) or any of its committees or working parties. Anna-Karin Berger is employed by Lundbeck A/S. Kim I. Bishop is the principal of Global Pharma Consultancy, LLC, a provider of CNS and cognitive psychopharmacology services with a particular focus on executive functioning. William P. Horan is an employee of and holds equity in Karuna Therapeutics. Christian Yavorksy is the Chief Scientific Officer at Valis Bioscience and reports no conflicts of interest. Monica Vance is the Chief Executive Officer of Santium Media Corporation and reports no conflicts of interest, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of adipose tissue of youth with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of adolescents with obesity but without diabetes, primary insulin hypersecretors had enhanced model-derived β-cell glucose sensitivity and rate sensitivity but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both oral glucose tolerance test and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher free fatty acid and leptin serum levels per fat mass, and faster in vivo lipid turnover assessed by a long-term 2H2O labeling protocol. At 2-year follow-up, hypersecretors had greater fat accrual and a threefold higher risk for abnormal glucose tolerance, while individuals with hypertrophic adipocytes or higher leptin levels showed enhanced β-cell glucose sensitivity. Primary insulin hypersecretion is associated with marked alterations in adipose tissue distribution, cellularity, and lipid dynamics, independent of whole-body adiposity and insulin resistance. Pathogenetic insight into the metabolic crosstalk between β-cell and adipocyte may help to identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance., (© 2024 by the American Diabetes Association.)

Objective: This study assessed the burden of Wilson Disease (WD) among patients and care partners (WD-CPs) in the US and compared it to a US general population of adults (GPs) and care partners (GP-CPs)., Methods: This cross-sectional, self-reported survey included patients with WD and WD-CPs aged ≥18 years recruited through the Wilson Disease Association (WDA), while data for GPs and GP-CPs were obtained from the 2022 National Health and Wellness Survey. GPs and GP-CPs were propensity score matched (3:1) with WD patients and WD-CPs for demographics and health characteristics. Bivariate analysis evaluated differences in comorbidity burden and health-related outcomes of the WD cohorts compared to matched GP cohorts., Results: Thirty-seven patients with WD and 53 WD-CPs completed the survey. Most patients reported some treatment burden (73.3%), experienced sleep problems (60%), and visited a healthcare provider (HCP) in the past 6 months (91.9%). Compared with matched GPs, patients with WD had a significantly higher mortality risk ( p < .001) and reported greater rates of chronic liver disease, cirrhosis (both, p < .001), migraines ( p = .032), non-alcoholic steatohepatitis ( p = .004), sleep problems ( p = .009) and HCP visits ( p = .002). Most WD-CPs (75.5%) reported high burden of caring (mean ZBI-12 score, 26.5) and more negative impact on esteem than GP-CPs., Conclusion: This study highlights the burden of WD experienced by patients and WD-CPs, with patients experiencing high treatment burden, comorbidity burden and healthcare resource utilization, and WD-CPs experiencing high impact of caring, including impact on employment and self-esteem.

Background: Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials., Results: This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease., Conclusions: This qualitative analysis provides a snapshot of clinicians' considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation., (© 2024. The Author(s).)

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and pre-clinical studies of FOP.