Evaluation and Application of a PET Tracer in Preclinical and Phase 1 Studies to Determine the Brain Biodistribution of Minzasolmin (UCB0599).

PURPOSE: Minzasolmin (UCB0599) is an orally administered, small molecule inhibitor of ASYN misfolding in development as a potential disease-modifying therapy for Parkinson's disease. Here we describe the preclinical development of a radiolabeled tracer and results from a phase 1 study using the tracer to investigate the brain distribution of minzasolmin. PROCEDURES: In the preclinical study, two radiolabeling positions were investigated on the S-enantiomer of minzasolmin (UCB2713): [11C]methylamine UCB2713 ([11C-N-CH3]UCB2713) and [11C]carbonyl UCB2713 ([11C-CO]UCB2713). Male C57 black 6 mice (N = 10) received intravenous [11C-N-CH3]UCB2713; brain homogenates were assessed for radioactivity and plasma samples analyzed by high-performance liquid chromatography. Positron emission tomography-computed tomography (PET-CT) was used to image brains in a subset of mice (n = 3). In the open-label, phase 1 study, healthy volunteers were scanned twice with PET-CT following injection with [11C]minzasolmin radiotracer (≤ 10 µg), first without, then with oral dosing with non-radiolabeled minzasolmin 360 mg. PRIMARY OBJECTIVE: to determine biodistribution of minzasolmin in the human brain; secondary objectives included minzasolmin safety/tolerability. RESULTS: Preclinical data supported the use of [11C]minzasolmin in clinical studies. In the phase 1 study, PET data showed substantial drug signal in the brain of healthy volunteers (N = 4). The mean estimated whole brain total distribution volume (VT) at equilibrium across all regions of interest was 0.512 mL/cm3, no difference in VT was observed following administration of minzasolmin 360 mg. Treatment-emergent adverse events (TEAEs) were reported by 75% (n = 3) of participants. No drug-related TEAEs, deaths, serious adverse events, or discontinuations were reported. CONCLUSION: Following positive preclinical results with the N-methyl labeled PET tracer, [11C]minzasolmin was used in the phase 1 study, which demonstrated that minzasolmin readily crossed the blood-brain barrier and was well distributed throughout the brain. Safety and pharmacokinetic findings were consistent with previous early-phase studies (such as UP0077, NCT04875962).

Phase 1/1b Studies of UCB0599, an Oral Inhibitor of α-Synuclein Misfolding, Including a Randomized Study in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) and its progression are thought to be caused and driven by misfolding of α-synuclein (ASYN). UCB0599 is an oral, small-molecule inhibitor of ASYN misfolding, aimed at slowing disease progression. OBJECTIVE: The aim was to investigate safety/tolerability and pharmacokinetics (PK) of single and multiple doses of UCB0599. METHODS: Safety/tolerability and PK of single and multiple doses of UCB0599 and its metabolites were investigated in two phase 1 studies in healthy participants (HPs), where food effect and possible interaction with itraconazole (ITZ) were assessed (UP0030 [randomized, placebo-controlled, dose-escalation, crossover study, N = 65] and UP0078 [open-label study, N = 22]). Safety/tolerability and multi-dose PK of UCB0599 were subsequently investigated in a phase 1b randomized, double-blind, placebo-controlled study of participants with PD (UP0077 [NCT04875962], N = 31). RESULTS: Across all studies, UCB0599 displayed rapid absorption with linear, time-independent PK properties; PK of multiple doses of UCB0599 were predictable from single-dose exposures. No notable food-effect was observed; co-administration with ITZ affected UCB0599 disposition (maximum plasma concentration and area under the curve increased ~1.3- and ~2 to 3-fold, respectively) however, this did not impact the safety profile. Hypersensitivity reactions were reported in UP0030 (n = 2) and UP0077 (n = 2). Treatment-related adverse events occurred in 43% (UCB0599), and 30% (placebo) of participants with PD were predominantly mild-to-moderate in intensity and were not dose related. CONCLUSIONS: Seventy-three HPs and 21 participants with PD received UCB0599 doses; an acceptable safety/tolerability profile and predictable PK support continued development of UCB0599 for the slowing of PD progression. A phase 2 study in early-stage PD is underway (NCT04658186). © 2022 UCB Pharma. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial.

BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear. METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15. RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) - 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified. CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.

Zilucoplan in patients with acute hypoxic respiratory failure due to COVID-19 (ZILU-COV): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. TRIAL DESIGN: This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study. PARTICIPANTS: Adult patients (≥18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows: 1) Inclusion criteria: a. Recent (≥6 days and ≤16 days) SARS-CoV-2 infection. b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation. c. Acute hypoxia (defined as PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen). d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those. 2) Exclusion criteria: e. Mechanical ventilation for more than 24 hours prior to randomisation. f. Active bacterial or fungal infection. g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways). INTERVENTION AND COMPARATOR: Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin. The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. MAIN OUTCOMES: The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A PO2 ratio. (PAO2= Partial alveolar pressure of oxygen, PaO2=partial arterial pressure of oxygen, FiO2=Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm. TRIAL STATUS: ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on May 11th, 2020 (ClinicalTrials.gov Identifier: NCT04382755 ) and on EudraCT (Identifier: 2020-002130-33 ). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

The influence of age, duration of symptoms and duration of operation on outcome after appendicitis in children.

INTRODUCTION: The aim of the study was to evaluate the impact of any perioperative parameters on the outcome of treatment for appendicitis. MATERIAL AND METHODS: The study included 108 consecutive children with appendicitis. Data were retrieved from files using the codes for appendectomy of the Nordic Classification of Surgical Procedures and the diagnosis codes for appendicitis from the International Classification of Dis-eases (ICD) 10. A non-satisfactory outcome was defined as a post-operative length of stay in hospital ≥ 5 days and/or readmission due to complications. RESULTS: Significantly more patients with a non-satisfactory outcome had complicated appendicitis (73%) compared with those with a satisfactory outcome (25%). A total of 78% of children < 6 years and 44% of children > 10 years had a non-satisfactory outcome. The duration of symptoms before operation was mean 2.8 days for children with a non-satisfactory outcome and 2.7 days for those with complicated appendicitis compared with 1.5 days for children with a satisfactory outcome and 1.6 days for those with simple appendicitis. The median difference was two days in the younger patients. Surgical time was significantly shorter in the group of patients with a satisfactory outcome and in those with simple appendicitis than in the other groups. CONCLUSION: Complicated appendicitis and a non-satisfactory outcome in children after operation are associated with a long preoperative duration of symptoms, young age and long surgical time. A cut-off age has not been established, but young children might benefit from direct referral and access to hospitalization in a regional or tertiary paediatric surgical centre. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

A biomechanical, histological and biochemical study in an experimental rabbit hypospadias repair model using scanning acoustic microscopy.

OBJECTIVE: To investigate the biomechanical, histological and biochemical properties of rabbit urethra at long-term follow up after hypospadias simulation and acute repair. MATERIALS AND METHODS: Thirty-eight white New Zealand male rabbits underwent experimental creation of a hypospadias-like defect and acute repair (mobilization and advancement, tubularized incised posterior urethral plate (TIP), modified TIP) and sham operation. After 23 weeks all groups + controls underwent biomechanical, histological and biochemical assessments. RESULTS: The mobilization and advancement group showed a higher stiffness compared to the TIP groups (P < 0.05) in the posterior urethra, whereas the TIP group was stiffer compared to the other two operative groups (P < 0.001) in the ventral urethra. In the dorsal urethra, the mobilization and advancement group and the modified TIP group had a higher collagen content compared to shams (P < 0.05). No differences in collagen content were found between groups in the ventral urethra. A correlation between acoustic and histological layers was found, partially related to collagen content. CONCLUSION: The urethras had different microelastic properties in different layers of the dorsal and ventral urethra, with higher stiffness in the connective tissue layers surrounding and within the urethra. The repaired urethras had partially recovered their elasticity at micrometer resolution at long-term follow up. Scanning acoustic microscopy elucidated structure-function relationships at microscopic level in normal and operated urethra.

In vivo biomechanical assessment of anterior rabbit urethra after repair of surgically created hypospadias.

PURPOSE: We studied the in vivo biomechanical properties of the anterior urethra in a rabbit hypospadias simulation model at long-term followup after urethroplasty. MATERIALS AND METHODS: A total of 38, 9-week-old white New Zealand male rabbits were randomized into active treatment and control groups. The active treatment group included hypospadias-like simulation and acute repair (sham, mobilization and advancement, tubularized incised posterior urethral plate). After 23 weeks all groups underwent biomechanical investigation using impedance planimetry. Cross-sectional area pressure measurements during bag distention were conducted at 3 different positions along the urethra, and biomechanical (tension-strain) relations were computed. The biomechanical parameters studied were urethral luminal dimension (cross-sectional area pressure relation) and its deformability to luminal pressure (tension-strain relation). RESULTS: The urethral cross-sectional area was significantly larger in the mobilization and advancement group compared to the tubularized incised plate group (p <0.001), shams and controls at the distal distention site (p <0.05), and other groups at the intermediate distention site (p <0.05). The strain-tension curves were not significantly different between the groups. CONCLUSIONS: All groups showed a nonlinear cross-sectional area pressure and circumferential wall tension-strain relationships in the 3 distention sites. The urethras exhibited a decreasing ability to be distended with increasing pressures, indicating self-protection against damage. At long-term followup no differences in tension-strain relations were found between groups, despite the fact that the mobilization and advancement group had enlarged urethras. Our hypospadias simulation animal model could be useful to test commonly used or new urethroplasty techniques and their functional (biomechanical) long-term results before clinical use.

Biomechanical and biochemical assessment of properties of the anterior urethra after hypospadias repair in a rabbit model.

PURPOSE: We created a rabbit model to test hypospadias operations and investigate the biomechanical properties of the urethra at long-term followup using biomechanical and biochemical assessments. MATERIALS AND METHODS: A total of 38 New Zealand White rabbits were randomized into 4 groups, including controls, sham operation and 2 operation groups (experimental creation of a hypospadias-like defect and acute repair, respectively). In operation group 1 the ventral urethral wall and dorsal plate were longitudinally incised, half of the ventral urethral wall was excised (hypospadias-like defect) and the incised urethra was tubularized (tubularized incised posterior plate urethroplasty group). In operation group 2 the urethra was mobilized from the corpora cavernosa, excised in its distal end (hypospadias-like defect) and advanced to the glanular tip (mobilization and advancement group). At 23 weeks postoperatively biochemical and biomechanical assessments were performed. RESULTS: Maximum urethral strength and stiffness, strain at maximum load and the collagen weight fraction were not significantly different among the groups. Urethral diameter was larger and the total amount of collagen was higher in the mobilization and advancement group only (p <0.05). The mechanical quality of urethral collagen was decreased in the 2 operation groups (p <0.05). CONCLUSIONS: This animal model proved to be useful for testing hypospadias operations and urethral mechanical properties. At long-term followup after experimental hypospadias repair biochemical and biomechanical assessments showed no differences among the groups in mechanical strength, strain and stiffness, and no indication of fibrosis. Consequently testing new hypospadias repair techniques and evaluating their biomechanical long-term results could be performed using hypospadiac animal models before clinical use.

Congenital symptomatic intrahepatic arteriovenous fistulas in newborns: management of 2 cases with prenatal diagnosis.

BACKGROUND: Fetal and neonatal hepatic arteriovenous fistulas are rare and associated with a high mortality rate; they can be prenatally detected by ultrasonography. Management of these malformations can be a challenge for pediatric surgeons. METHODS: Two patients with a prenatal diagnosis of intrahepatic arteriovenous shunts were treated at our institution in the last 2 years. A hepatic complex arteriovenous malformation fed respectively by prominent branches of the hepatic artery and of the celiac trunk rising from dilated suprarenal aortae and draining into suprahepatic veins was detected. In the first case, an embolization was performed; in the second, the surgical resection of the vascular malformation was the treatment of choice. RESULTS: The first patient died after embolization and before surgery for hemodynamic complications. The second patient, at a follow-up of 16 months, is alive and doing well. CONCLUSION: Hepatic resection is the treatment of choice for localized intrahepatic arteriovenous malformation. Theoretically, embolization could be curative or reduce the size of a malformation, making consequent hepatic resection feasible. Results do not support this theory because of the high rate of complications recorded that brought in every case, ours included, to the death of the child.

A new method to correlate histology with biomechanical properties in urethral tissue. An in-vitro study using light microscopy and scanning acoustic microscopy.

When surveying the classical biomechanical theory of flow and resistance, the passive elastic properties of the urethra seems to be important for the transport of urine though the urethra. The aim of this study was to show that scanning acoustic microscopy (SAM) is a suitable methodology for investigating elastic properties of the urethra, and that it can be used to correlate elastic properties to histological areas. One 40 kg female pig and one 2 kg male rabbit comprised the material. A SAM2000 was used at a working frequency of 1000 MHz. Sections of nominal 3 micrometer thickness fixed urethral tissue were prepared for SAM and stained for light microscopy. The histological layers of the urethra were evident in the SAM image, and showed highly variable values of elastic properties. The layers seen with SAM correlated well with those seen with light microscopy. In conclusion, we have provided the first images of the microelastic properties of the urethra and correlated them to histology.