Grifols (Spain)

BackgroundABvac40 is an investigational vaccine targeting Aβ40 for the treatment of Alzheimer’s disease (AD). Aβ40 plays a significant role in several pathological processes of AD, especially concerning amyloid deposition in blood vessels. Phase 2 trial results (NCT03461276) demonstrated a favorable safety profile, robust immunogenicity, and promising trends in cognitive outcomes and brain atrophy. To further explore the therapeutic potential of ABvac40, we aimed to assess clinical relevance at individual patient level by evaluating meaningful within‐patient changes (MWPC). This approach examines the proportion of patients experiencing significant deterioration across treatment groups, providing a method to assess the meaningfulness of treatment effects in progressive conditions like AD.MethodAB1601 was a randomized, double‐blind, placebo‐controlled phase 2 study in patients with mild cognitive impairment or very mild AD. MWPC was defined as a decline of ≥3 points in MMSE at two consecutive visits over 24 months. Cox proportional hazard models assessed the risk of MWPC, adjusting for MMSE baseline score, baseline age, APOE Ɛ4 carrier status, clinical stage and baseline use of AD medication. Patients treated with ABvac40 were stratified by CSF antibody levels into two groups: high levels (Q4) and low levels (Q1–Q3). Analyses were conducted in the PPc analysis set.ResultA total of 97 patients were included in the PPc analysis set. Of these, 69 (71.1%) were amyloid‐PET positive. In the overall population, ABvac40 significantly reduced the risk of MWPC over 24 months compared to placebo (HR=0.47; 95% CI 0.27–0.85; P=0.012). In the amyloid‐PET positive subgroup, ABvac40 showed a more pronounced protective effect (HR=0.38; 95% CI 0.20‐0.75; P=0.005). Within this subgroup, patients with lower antibody levels had a 63% lower risk of MWPC (HR=0.37; 95% CI 0.16–0.83; P=0.016), while those with higher antibody levels showed an 81% reduction (HR=0.19; 95% CI 0.04–0.84; P=0.029).ConclusionABvac40 treatment significantly reduced clinically meaningful cognitive decline, particularly in amyloid‐PET positive patients, with the strongest effects in those with the highest antibody levels. These findings highlight ABvac40’s potential to influence disease progression in early‐stage AD and warrant further studies to explore its impact on brain vessels as potential driver of the observed cognitive benefits.

INTRODUCTIONABvac40 is an investigational active immunotherapy (vaccine) targeting Aβ40. This study assessed the safety and immunogenicity of ABvac40 in patients with amnestic mild cognitive impairment or very mild Alzheimer's disease.METHODSAB1601 was a multicenter, randomized, double‐blind, placebo‐controlled phase 2 study. Patients (n = 124) received five monthly injections plus a 10‐month booster of ABvac40 or placebo, with 18–24 months of follow‐up. Primary endpoints included safety, tolerability, and immunogenicity. Secondary endpoints assessed immune response, neuropsychological changes, and disease biomarkers.RESULTSTreatment‐emergent adverse events (TEAEs) and serious TEAEs were comparable between ABvac40 (90.6% and 26.6%) and placebo (93.3% and 26.7%). Amyloid‐related imaging abnormalities‐hemorrhage (ARIA‐H) were similar (12.5% ABvac40; 15.0% placebo), with no ARIA‐edema (ARIA‐E) or meningoencephalomyelitis. ABvac40 induced a specific, sustained immune response in plasma, with detectable antibodies in CSF.DISCUSSIONThese findings support further investigation of ABvac40 as a potential disease‐modifying therapy.Clinical Trial Registration Number: NCT03461276 (ClinicalTrials.gov)HighlightsABvac40 was safe and well‐tolerated in early‐stage Alzheimer's disease patients.No amyloid‐related imaging abnormalities‐edema (ARIA‐E) or encephalitis observed; ARIA‐hemorrhage (ARIA‐H) rates were similar across groups.Specific, sustained immune response to ABvac40 in plasma, with cerebrospinal fluid (CSF) antibody penetration.Cognitive scales and magnetic resonance imaging (MRI) volumetric data favored ABvac40 over placebo.Results support further development of ABvac40 as a disease‐modifying therapy.

Abstract Patients with acute decompensation (AD) of cirrhosis face a high risk of acute-on-chronic liver failure (ACLF), a syndrome linked to multiple organ failure and high mortality. This study analyzed peripheral blood mononuclear cells (PBMCs) using single-cell technologies to explore their role in patient outcomes. Blood samples from 15 healthy donors and 63 AD patients were prospectively collected at hospital admission across five European centers, with patients monitored for 90 days. CITE-seq was performed on PBMCs from 4 controls and 16 patients representing different disease trajectories. A rise in classical monocytes, particularly subcluster “C2,” was noted in patients progressing to ACLF. This subset showed impaired energy metabolism, with reduced oxidative phosphorylation and ATP production. Notably, genes coding for Complex IV of the respiratory chain were significantly downregulated. In two large prospective international cohorts (PREDICT, n=689; ACLARA, n=521), we observed that a gene signature from C2 was elevated in patients with cirrhosis with bacterial infections, ACLF, and in non-survivors. Functional validation of our findings was performed using respirometry analyses in an independent AD cohort, specifically evaluating mitochondrial function in the total classical monocyte population. A progressive decline in Complex IV-driven oxygen consumption rate (OCR) was observed in pre-ACLF patients. In conclusion, we idenofied and validated that paoents with AD having a poor outcome are characterized by a subpopulaoon of monocytes with impaired energy metabolism. This cell populaoon might contribute to the transioon from AD to ACLF.TeaserA unique monocyte subset with metabolic dysfunction is associated with disease progression in patients with acute decompensation of cirrhosis.

Hemophilia A (HA) patients under emicizumab prophylaxis may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction (ITI). The aim of this study is to evaluate the ex vivo procoagulant effect of plasma-derived FVIII concentrates containing von Willebrand factor (pdFVIII/VWF) in samples from patients with severe HA without inhibitors on emicizumab prophylaxis. Samples from healthy controls (HC) and HA patients were drawn in sodium citrate plus corn trypsin inhibitor tubes and spiked with increasing concentrations of pdFVIII/VWF concentrates (10–400 IU/dL) (Fanhdi®/Alphanate®, Grifols), activated prothrombin complex concentrate (aPCC, 0.5 U/mL) or recombinant activated factor VII (rFVIIa, 0.9 µg/mL). Global coagulation was measured by rotational thromboelastometry (ROTEM) (clotting time [CT] and time to maximum clot formation velocity [MAXV-t]) and thrombin generation (TG) assay (thrombin peak [TP] and endogenous thrombin potential [ETP]). Samples from HA patients under emicizumab prophylaxis showed CT and MAXV-t values above HC levels, while TP and ETP were below HC levels. Ex vivo pdFVIII/VWF supplementation increased TP and ETP and shortened CT and MAXV-t dose-dependently. At 50 IU/dL (≈25 IU/kg), pdFVIII/VWF normalized clot formation and restored TG within HC normal range. The highest pdFVIII/VWF concentration (400 IU/dL) and rFVIIa did not result in an excessive procoagulant profile. However, aPCC induced ex vivo an excessive TG and markedly decreased ROTEM parameters (CT and MAXV-t). Coagulation parameters of both methods significantly correlated at baseline and with increasing concentrations of pdFVIII/VWF. High doses of pdFVIII/VWF concentrates, similar to those used for ITI, did not trigger a multiplying procoagulant effect to samples from HA patients on emicizumab prophylaxis, evidencing their low thrombotic risk in these patients.Graphical abstract

Prospective, randomized, controlled trials of intravenous immunoglobulin (IVIG) maintenance therapy in myasthenia gravis (MG) are lacking. In this trial, we evaluated the safety and efficacy of caprylate/chromatography-purified IVIG; (IGIV-C) in patients with generalized MG undergoing standard care. Sixty-two patients enrolled in this phase 2, multicenter, international, randomized trial (1:1 IGIV-C [2 g/kg loading dose; 1 g/kg every 3 weeks through week 21] or placebo). Efficacy was assessed by changes in Quantitative MG (QMG) score at week 24 versus baseline (primary endpoint) and percentage of patients with clinical improvement in QMG, MG Composite (MGC), and MG-Activities of Daily Living (MG-ADL) scores (secondary endpoints). Safety assessments reported all adverse events (AEs). The change in QMG at 24 weeks was -5.1 for IGIV-C and -3.1 for placebo (p = .187). Seventy percent of patients in the IGIV-C group had improvement in MG-ADL (≥2-point decrease) versus 40.6% in the placebo group (p = .025). Patients showing clinical improvement in QMG and MGC (≥3-point decrease) were 70.0% for IGIV-C versus 59.4% for placebo (p = .442) and 60.0% for IGIV-C versus 53.1% for placebo (p = .610). IGIV-C was well tolerated; serious AEs were similar between arms. Three of four MG exacerbations requiring hospitalizations occurred in the IGIV-C arm with one death. Several efficacy parameters showed numerical results greater than those seen in the placebo group. This was a small study and may have been underpowered to see significant differences. Additional studies may be warranted to fully determine the efficacy of IVIG maintenance therapy in MG.

BackgroundTrimodulin (human polyvalent immunoglobulin [Ig] M ~ 23%, IgA ~ 21%, IgG ~ 56% preparation) has previously been associated with a lower mortality rate in a subpopulation of patients with severe community-acquired pneumonia on invasive mechanical ventilation (IMV) and with clear signs of inflammation. The hypothesis for the ESsCOVID trial was that trimodulin may prevent inflammation-driven progression of severe coronavirus disease 2019 (COVID-19) to critical disease or even death.MethodsAdults with severe COVID-19 were randomised to receive intravenous infusions of trimodulin or placebo for 5 consecutive days in addition to standard of care. The primary efficacy endpoint was a composite of clinical deterioration (Days 6–29) and 28-day all-cause mortality (Days 1–29).ResultsOne-hundred-and-sixty-six patients received trimodulin (n = 84) or placebo (n = 82). Thirty-three patients died, nine during the treatment phase. Overall, 84.9% and 76.5% of patients completed treatment and follow-up, respectively. The primary efficacy endpoint was reported in 33.3% of patients on trimodulin and 34.1% of patients on placebo (P = 0.912). No differences were observed in the proportion of patients recovered on Day 29, days of invasive mechanical ventilation, or intensive care unit-free days. Rates of treatment-emergent adverse events were comparable.A post hoc analysis was conducted in patients with early systemic inflammation by excluding those with high CRP (> 150 mg/L) and/or D-dimer (≥ 3 mg/L) and/or low platelet counts (< 130 × 109/L) at baseline. Forty-seven patients in the trimodulin group and 49 in the placebo group met these criteria. A difference of 15.5 percentage points in clinical deterioration and mortality was observed in favour of trimodulin (95% confidence interval: −4.46, 34.78; P = 0.096).ConclusionAlthough there was no difference in the primary outcome in the overall population, observations in a subgroup of patients with early systemic inflammation suggest that trimodulin may have potential in this setting that warrants further investigation.ESsCOVID was registered prospectively at ClinicalTrials.gov on October 6, 2020.NCT04576728

Disease progression in Alzheimer's Dementia (AD) is typically characterized by accelerated cognitive and functional decline, where heterogeneous trajectories can impact the observed treatment response. We hypothesized that unobserved heterogeneity could obscure treatment benefits in AD. The effect of unobserved heterogeneity was empirically quantified within the Alzheimer's Management By Albumin Replacement (AMBAR) phase 2b trial data. The ADAS-Cog 12 cognition endpoint was reanalyzed in a 2-class latent growth mixture model initially fit to the treatment arm. The model with the best fit was then applied across both treatment arms to a larger (n=1000) simulated dataset that was representative of AMBAR trial cognitive data. Two classes of patients were observed: a stable cognitive trajectory class and a highly variable class. Removal of the latter (n=48, 22%) from the analysis and refitting efficacy models comparing the stable class to full placebo yielded significant treatment efficacy on cognition (p=0.007, Cohen's D=-0.4). Comparison of the stable class of each arm within the simulated dataset revealed a significant difference in treatment efficacy favoring the simulated stable treatment arm. This post hoc exploratory analysis suggests that prespecified strategies for addressing unobserved heterogeneity may yield improved effect detection in AD trials. The generalizability of the analytic strategy is limited by latent stratification in only the treatment arm, a requirement given the small placebo arm in AMBAR. This limitation was partially addressed by the simulation modeling.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.