Randomized Phase I Trial of the α-Synuclein Antibody Lu AF82422.

BACKGROUND: Immunotherapy targeting pathological α-synuclein (α-syn) species is a promising strategy for slowing disease progression in neurodegenerative synucleinopathies, including Parkinson's disease (PD). OBJECTIVE: The aim was to evaluate the safety, tolerability, pharmacokinetics, and target engagement of ascending doses of Lu AF82422. METHODS: In this first-in-human study (NCT03611569), healthy participants (18-55 years, cohort A) and patients with PD (40-80 years, Hoehn and Yahr stage ≤3, cohort B) were enrolled in ascending-dose cohorts and randomly assigned to receive single intravenous infusions of Lu AF82422 (cohorts A1-A6: 75, 225, 750, 2250 4500, and 9000 mg, respectively; cohorts B1 and B2: 2250 and 9000 mg, respectively) or placebo. Participants were monitored during a 12-week observational period. RESULTS: Overall, single intravenous infusions of Lu AF82422 were safe and well tolerated, and no serious adverse events (AE) were observed; the most common AEs were related to the study on lumbar punctures, headache, and common infections. Lu AF82422 concentrations (in plasma and cerebrospinal fluid [CSF]) increased in a dose-proportional manner with no observable differences between cohorts; mean plasma half-life was 700 h. Plasma concentrations of Lu AF82422 had an immediate, concentration-dependent lowering effect on the plasma concentration of free α-syn and on the ratio of free to total α-syn in all cohorts and lowered the free-to-total α-syn ratio in CSF in the high-dose PD cohort. CONCLUSIONS: The safety and pharmacokinetic profile of Lu AF82422 were appropriate for further clinical development, and results indicated peripheral target engagement. The central target engagement observed in participants with PD indicates that the doses of Lu AF82422 tested may provide CSF concentrations sufficient to target aggregated forms of α-syn. © 2024 H. Lundbeck A/S. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Enzymatic activity of extracellular circulating proteasome in the CSF of patients with malignant Intrinsic and metastatic brain tumors: proof of concept.

BACKGROUND: Malignant intrinsic brain tumors are a hazardous disease with limited life expectancy despite intensive research in new targeted treatment options. Lately, proteasome inhibitors have been identified as potent agents causing death in glioma cell lines. It is the aim of the present study to identify proteasomal activity in the CSF of patients suffering from malignant brain tumors. METHODS: A total of 24 patients with histological confirmed brain tumors (12 malignant gliomas, 12 metastases) were included and CSF probes preoperatively analyzed for concentration and enzymatic activity of free circulating proteasome. Tumor volumina were assessed using the preoperative MRI and correlated with the CSF findings. Statistical analyses were performed using SPSS (18.0.3; SPSS Inc., Chicago, IL, USA). RESULTS: Extracellular proteasomes were found in all CSF samples showing enzymatic activity. Proteasome concentrations (28 ng/mL and 23 ng/mL, resp.) were elevated compared to a historical control group. Proteasomal enzymatic chymotrypsin-like activity was significantly raised in patients with gliomas (mean 31 fkat/ mL) compared to controls (P<0.049), whereas the enzymatic activity was not significantly elevated in metastases (P=0.109). In gliomas, neither concentration nor enzymatic activity correlated with the preoperative assessed tumor volume. CONCLUSIONS: This pilot study clearly showed that the proteasomal activity in the CSF is significantly elevated in patients with intrinsic brain tumors. Further studies need to identify the proteasomal concentration and enzymatic activity as a potential biomarker for the effectiveness of any treatment and for the early diagnosis of a possible recurrence of the disease.

Circulating extracellular proteasome in the cerebrospinal fluid: a study on concentration and proteolytic activity.

Alterations of the intracellular ubiquitin-proteasome pathway are found in neurodegenerative and inflammatory disorders of the central nervous system, as well as in its malignancies. Inhibitory substrates of the proteasomes represent promising approaches to control autoimmune inflammations and induction of apoptosis in cancer cells. Extracellular circulating proteasomes are positively correlated to outcome prognosis in hematogenic neoplasias and the outcome in critically ill patients. Previously, we reported raised levels of proteolytic active 20S proteasomes in the extracellular alveolar space in patients with acute respiratory distress syndrome (ARDS). For the cerebrospinal fluid, we assumed that extracellular circulating proteasomes with enzymatic activity can be found, too. Cerebrospinal fluid (CSF) samples of twenty-six patients (14 females, 12 males), who underwent diagnostic spinal myelography, were analyzed for leukocyte cell count, total protein content, lactate and interleukine-6 (Il-6) concentrations. CSF samples were analyzed for concentration and enzymatic activity of extracellular 20S proteasomes (fluorescenic substrate cleavage; femtokatal). Blood samples were analyzed with respect to concentration of extracellular circulating proteasomes. Choroidal plexus was harvested at autopsies and examined with immunoelectron microscopy (EM) for identification of possible transportation mechanisms. Statistical analysis was performed using SPSS (18.0.3). In all patients, extracellular proteasome was found in the CSF. The mean concentration was 24.6 ng/ml. Enzymatic activity of the 20S subunits of proteasomes was positively identified by the fluorescenic subtrate cleavage at a mean of 8.5 fkat/ml. Concentrations of extracellular proteasomes in the CSF, total protein content and Il-6 were uncorrelated. Immunoelectron microscopy revealed merging vesicles of proteasomes with the outer cell membrane suggestive of an exozytic transport mechanism. For the first time, extracellular circulating 20S proteasome in the CSF of healthy individuals is identified and its enzymatic activity detected. A possible exozytic vesicle-bond transportation mechanism is suggested by immunoelectron microscopy. The present study raises more questions on the function of extracellular proteasome in the CSF and encourages further studies on the role of extracellular protesomes in pathological conditions of the central nervous system (tumor lesions and inflammatory processes).

Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies.

PURPOSE: Thromboembolism is a major source of morbidity and mortality in patients with cancer. The contribution of anti-vascular endothelial growth factor therapy to these events remains controversial. PATIENTS AND METHODS: Individual patient data were available for 6,055 patients in 10 randomized studies. Unadjusted and exposure-adjusted incidence of venous thromboembolisms (VTEs) was estimated for the overall population and by tumor type. Multivariate analysis was performed to identify risk factors for development of VTE. The safety of anticoagulant therapy in patients undergoing bevacizumab treatment was also examined. RESULTS: There were no statistically significant increases in the unadjusted or exposure-adjusted incidences of all-grade VTEs for bevacizumab versus controls in the overall population or by tumor type. The unadjusted incidence in the overall population was 10.9% with bevacizumab versus 9.8% with controls (odds ratio, 1.14; 95% CI, 0.96 to 1.35; P = .13); the rate per 100 patient-years was 18.5 for bevacizumab and 20.3 for controls (rate ratio, 0.91; 95% CI, 0.77 to 1.06; P =.23). Incidences of grade 3 to 5 events were similar in both groups. Several risk factors for VTEs were identified, including tumor type, older age, poorer performance status, VTE history, and baseline oral anticoagulant use. No interactions between bevacizumab treatment and these factors were observed. For patients who had a VTE and received full-dose anticoagulation therapy, the risk of severe bleeding was low (< 1%) and unaffected by bevacizumab treatment. CONCLUSION: The addition of bevacizumab to chemotherapy did not statistically significantly increase the risk of VTEs versus chemotherapy alone. The risk for VTEs is driven predominantly by tumor and host factors.

OPPORTUNITY: a randomized clinical trial of growth hormone on outcome in hemodialysis patients.

BACKGROUND: The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health-related quality of life (HRQoL), which are significantly and positively associated with survival in MHD patients. The OPPORTUNITY Trial will examine whether GH reduces mortality and morbidity and improves overall health in hypoalbuminemic MHD patients. HYPOTHESIS: The primary hypothesis is that daily recombinant human GH injections, compared with placebo, improve survival in hypoalbuminemic MHD patients. Secondary hypotheses are that GH improves morbidity and health, including number of hospitalized days, time to cardiovascular events, LBM, serum protein and inflammatory marker levels, exercise capacity, and HRQoL, and has a favorable safety profile. DESIGN/MEASUREMENTS: This is a prospective, double-blind, multicenter, randomized clinical trial involving 2500 MHD patients, up to 50% with diabetes mellitus, from 22 countries. Patients are randomized in a 1:1 ratio to receive daily injections of GH (20 microg/kg per day) or placebo for 104 weeks. Key inclusion criteria include clinically stable and well-dialyzed (Kt/V > or =1.2) adult MHD patients with serum albumin <4.0 g/dl. Exclusion criteria include active malignancy, active proliferative or severe nonproliferative diabetic retinopathy, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy. CONCLUSIONS: The OPPORTUNITY Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers of body protein mass, inflammation, exercise capacity, and HRQoL.

Growth hormone treatment during hemodialysis in a randomized trial improves nutrition, quality of life, and cardiovascular risk.

Nutritional markers, such as lean body mass (LBM) and serum albumin, predict outcome in dialysis patients, in whom protein-energy malnutrition is associated with increased morbidity and mortality. The metabolic effects of human growth hormone (hGH) may improve the nutritional and cardiovascular health of these patients and consequently reduce morbidity and mortality. The aim of this study was to establish clinical proof of concept of hGH treatment for the improvement of the nutritional status in adult patients who are on maintenance hemodialysis. A total of 139 adult patients who were on maintenance hemodialysis and had serum albumin levels < or =40 g/L were randomly assigned to 6 mo of treatment with placebo or 20, 35, or 50 microg/kg per d hGH. Change in LBM and serum albumin (primary outcomes), health-related quality of life, and secondary efficacy and safety parameters were monitored. The study showed that hGH treatment increased LBM significantly at all dosage levels (2.5 kg [95% confidence interval 1.8 to 3.1] versus -0.4 kg [95% confidence interval -1.4 to 0.6]; P < 0.001 for pooled hGH groups versus placebo). Serum albumin tended to increase (P = 0.076), serum transferrin (P = 0.001) and serum HDL (P < 0.038) increased, and plasma homocysteine was reduced (P = 0.029). TNF-alpha also tended to decrease with treatment (P = 0.134). An improvement in the Role Physical SF-36 quality-of-life subscale was observed (P = 0.042). There were no differences in clinically relevant adverse events between groups. In conclusion, hGH therapy safely improves LBM, other markers of mortality and morbidity, and health-related quality of life in adult patients who are on maintenance hemodialysis. A long-term study is warranted to investigate whether these treatment benefits result in reduced mortality and morbidity.