Prothena (United States)

Background: Targeted muscle reinnervation (TMR) is increasingly used to enhance prosthetic control and to reduce post-amputation pain. Its implementation across new centers raises questions about the reproducibility of outcomes and the impact of surgical experience. Methods: We compared the first three TMR patients treated in a newly established center in Nantes, France, with three patients treated in a high-volume center in Göttingen, Germany. Functional outcomes were measured using the Box and Block test (BBT), and operative time was recorded. Two French cases were performed with the assistance of a Göttingen-based surgeon. Conclusions: The functional outcomes showed a similar trend in both groups. The mean BBT scores were equivalent, suggesting reliable reinnervation and prosthetic integration even in early cases. Operative times were longer in Nantes, but did not impact outcomes. TMR appears not to have a pronounced learning curve, particularly regarding functional success in early cases under guided protocols. Factors such as assistance from experienced surgeons and favorable donor-to-recipient nerve ratios likely contribute to consistent outcomes. These findings support the reproducibility of TMR across institutions. Results: Within the first two years of rehabilitation we observed improvements in both functional performance and patient-reported quality of life. All six patients across both centers in-creased in BBT scores. All the patients reported an increase in social relationships and psychological health, and two of three patients reported an increase in physical health. Importantly, all six patients discontinued the use of pain medication at 2 years fol-lowing TMR. Furthermore, the French patients reported a decrease from 65–82 mm to 0–31 mm across the patients’ Visual Analog Scale (VAS) pain scores.

ABSTRACTIn practice, the use of rounding is ubiquitous. Although researchers have looked at the implications of rounding continuous random variables, rounding may also be applied to functions of discrete random variables. For example, to infer the number of excess deaths due to falls after a national emergency, authorities may only provide a rounded average of deaths before and after the emergency started. Deaths from falling tend to be relatively low in most places, and such rounding may seriously affect inference on the change in the rate of deaths. In this paper, we study drawing inference on a parameter from the probability mass function of a non‐negative discrete random variable , when for rounding coarsening width we get as a proxy for . We show that the probability generating function of , , and capture the effect of the coarsening of the support of . Theoretical properties are explored further under some probability distributions. Moreover, we introduce two relative risks of rounding metrics to aid the numerical assessment of how sensitive the results may be to rounding. Under certain conditions, rounding has little impact. However, we also find scenarios where rounding can significantly affect statistical inference. The methods are applied to infer the probability of success of a binomial distribution and estimate the excess deaths due to Hurricane Maria. The simple methods we propose can partially counter rounding error effects.

e13574 Background: AL (amyloid light chain) amyloidosis is associated with poor prognosis especially if diagnosis occurs with cardiac involvement. Current AL treatments target the plasma cell clone producing the light chains that misfold, aggregate and deposit in various tissues. The multi-organ manifestations of AL amyloidosis require a multidisciplinary care team of hematologist-oncologists, cardiologists, and other healthcare providers (HCPs) for comprehensive, patient-centric management. Since 2022, Amyloidosis Stakeholder Partnerships for Impact, Reach & Equity (ASPIRE), facilitated by Amyloidosis Research Consortium (ARC) has been bringing together biotech and pharmaceutical companies with the shared goal of optimizing amyloidosis patient care. Through this study, ARC-ASPIRE sought to document and share the current best practices and key barriers to patient-centric amyloidosis care at US specialized amyloidosis centers (SACs). A broad range of stakeholders in amyloidosis care – healthcare providers at SACs, patients, referring physicians, and patient advocacy group representatives – were interviewed for this study. This abstract presents findings relevant to the management of patients with AL amyloidosis. Methods: Structured interviews were conducted between December 2023 and February 2024 with 77 amyloidosis stakeholders (physicians, advanced practice providers, registered nurses from 17 SACs, patients, referring physicians, and patient advocacy group representatives), including 12 hematology-oncologists and 8 AL patients. SACs were selected to be representative of current US amyloidosis care, based on geography, amyloidosis patient volume, years since establishment, and types of amyloidosis treated. Results: Three-quarters of participating SACs treat AL patients under a single multidisciplinary amyloidosis program. Multidisciplinary care is facilitated by regular team meetings, dedicated clinic days, and informal communications across specialties. At diagnosis, collaboration between cardiology and hematology-oncology ensures AL patients are accurately diagnosed and promptly treated. Sixty percent of SACs have a centralized intake system, and patients suspected with AL are prioritized to ensure an appointment within 1 week of referral. Key barriers were delayed or missed diagnosis due to low awareness of AL amyloidosis within community oncologists, travel burden to SACs, lack of seamless medical records sharing and telehealth regulations. Conclusions: The best practices outlined in this study serve to educate AL amyloidosis and non-AL amyloidosis HCPs for better multidisciplinary collaboration and early diagnosis. The key barriers identified should be addressed to improve patient care.

Background The investigational monoclonal antibody PRX004 is designed to specifically target and deplete TTR amyloid. Here, we report on the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary clinical activity of PRX004 in patients with ATTRv amyloidosis. Methods This global, multicentre, phase 1 trial comprised a 3 + 3 dose-escalation phase and a long-term extension (LTE) phase (NCT03336580). In the dose-escalation phase, patients received PRX004 (0.1, 0.3, 1, 3, 10 or 30 mg/kg), administered intravenously every 28 days for 3 months. In the LTE, eligible patients could receive up to 15 additional doses. Patients who received doses of ≥3 mg/kg for ≥9 months were assessed for Global Longitudinal Strain (GLS) and Neuropathy Impairment Score (NIS). The primary objective was to determine the maximum tolerated dose (MTD) of PRX004. Results Overall, 21 patients with ATTRv amyloidosis completed the dose-escalation phase; 17 subsequently enrolled in the LTE. The MTD was not reached. PRX004 was well tolerated at all doses, with dose-proportional exposure. GLS and NIS were improved or maintained over 9 months (n = 7). Conclusions PRX004 was well tolerated in patients with ATTRv amyloidosis and demonstrated potential clinical activity. A phase 2 randomised controlled trial in ATTR cardiomyopathy is ongoing (NCT05442047).

Systemic AL (light chain) amyloidosis is a rare protein misfolding disorder associated with plasma cell dyscrasia affecting various organs leading to organ dysfunction and failure. The Amyloidosis Forum is a public-private partnership between the Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research with the goal of accelerating the development of effective treatments for AL amyloidosis. In recognition of this goal, 6 individual working groups were formed to identify and/or provide recommendations related to various aspects of patient-relevant clinical trial endpoints. This review summarizes the methods, findings, and recommendations of the Health-Related Quality of Life (HRQOL) Working Group. The HRQOL Working Group sought to identify existing patient-reported outcome (PRO) assessments of HRQOL for use in clinical trials and practice deemed relevant across a broad spectrum of patients with AL amyloidosis. A systematic review of the AL amyloidosis literature identified 1) additional signs/symptoms not currently part of an existing conceptual model, and 2) relevant PRO instruments used to measure HRQOL. The Working Group mapped content from each identified instrument to areas of impact in the conceptual model to determine which instrument(s) provide coverage of relevant concepts. The SF-36v2® Health Survey (SF-36v2; QualityMetric Incorporated, LLC) and Patient-Reported Outcomes Measurement Information System-29 Profile (PROMIS-29; HealthMeasures) were identified as instruments relevant to patients with AL amyloidosis. Existing evidence of reliability and validity was evaluated with a recommendation for future work focused on estimating clinically meaningful within-patient change thresholds for these instruments. For sponsors, the context of use-including specific research objectives, trial population, and investigational product under study-should inherently drive selection of the appropriate PRO instrument and endpoint definitions to detect meaningful change and enable patient-focused drug development.

TPS8076 Background: Light chain (AL) amyloidosis is a progressive and typically fatal disorder caused by misfolded AL protein produced by plasma cells. Birtamimab is a monoclonal antibody designed to neutralize circulating soluble and deposited insoluble amyloid, thus promoting phagocytic clearance. In 2018, the phase 3 VITAL study in newly diagnosed, treatment-naive patients was terminated based on futility analysis of the primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization > 90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.835 [95% CI: 0.5799, 1.2011]; p = 0.330). Post-hoc analysis of ACM over 9 months revealed a substantial survival benefit (HR = 0.413 [95% CI: 0.191, 0.895]; p = 0.025) in patients at high risk for early death (Mayo Stage IV). Post-hoc analyses of secondary endpoints in this subgroup indicated meaningful improvements in health-related quality of life (assessed with 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance with birtamimab + SOC (p < 0.05) at 9 months. Methods: The phase 3, double-blind, placebo-controlled AFFIRM-AL study (NCT04973137) will enroll up to 150 Mayo Stage IV patients with newly diagnosed, untreated AL amyloidosis. Patients will be randomized (2:1) to 24 mg/kg intravenous birtamimab or placebo every 28 days. Both arms will receive concomitant chemotherapy with a first-line bortezomib-containing regimen, with or without daratumumab (D), at the discretion of the investigator. Patients will be stratified at randomization based on their 6MWT distance ( < 300 vs ≥300 meters) and initiation of D. The primary efficacy endpoint is time to ACM. Secondary endpoints are change from baseline to month 9 in the physical component summary of the SF-36v2 and 6MWT distance. This trial is powered at a significance level of 0.1 under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). Given the > 50% relative risk reduction for ACM observed in the post-hoc analysis of VITAL for patients with Mayo Stage IV disease, the AFFIRM-AL study is designed to confirm this effect of birtamimab. Approximately 130 global sites are planned; site initiation and patient randomization are underway. Conclusion: Treatments that improve survival in AL amyloidosis are needed, particularly for patients with advanced cardiac involvement, as median overall survival for those with Mayo Stage IV disease is ̃6–9 months. The AFFIRM-AL study is designed to confirm the survival benefit observed in the VITAL study in patients with Mayo Stage IV AL amyloidosis. Clinical trial information: NCT04973137.

Various post-translationally modified (PTM) proteoforms of alpha-synuclein (aSyn)—including C-terminally truncated (CTT) and Serine 129 phosphorylated (Ser129-p) aSyn—accumulate in Lewy bodies (LBs) in different regions of the Parkinson’s disease (PD) brain. Insight into the distribution of these proteoforms within LBs and subcellular compartments may aid in understanding the orchestration of Lewy pathology in PD. We applied epitope-specific antibodies against CTT and Ser129-p aSyn proteoforms and different aSyn domains in immunohistochemical multiple labelings on post-mortem brain tissue from PD patients and non-neurological, aged controls, which were scanned using high-resolution 3D multicolor confocal and stimulated emission depletion (STED) microscopy. Our multiple labeling setup highlighted a consistent onion skin-type 3D architecture in mature nigral LBs in which an intricate and structured-appearing framework of Ser129-p aSyn and cytoskeletal elements encapsulates a core enriched in CTT aSyn species. By label-free CARS microscopy we found that enrichments of proteins and lipids were mainly localized to the central portion of nigral aSyn-immunopositive (aSyn+) inclusions. Outside LBs, we observed that 122CTT aSyn+ punctae localized at mitochondrial membranes in the cytoplasm of neurons in PD and control brains, suggesting a physiological role for 122CTT aSyn outside of LBs. In contrast, very limited to no Ser129-p aSyn immunoreactivity was observed in brains of non-neurological controls, while the alignment of Ser129-p aSyn in a neuronal cytoplasmic network was characteristic for brains with (incidental) LB disease. Interestingly, Ser129-p aSyn+ network profiles were not only observed in neurons containing LBs but also in neurons without LBs particularly in donors at early disease stage, pointing towards a possible subcellular pathological phenotype preceding LB formation. Together, our high-resolution and 3D multicolor microscopy observations in the post-mortem human brain provide insights into potential mechanisms underlying a regulated LB morphogenesis.

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease.