Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease

Introduction: CAD106 is designed to stimulate amyloid-β (Aβ)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first-in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections. Methods: Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66-week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer’s disease (AD) aged 40 to 85 years. Patients were randomized to receive 150μg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 μg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Aβ-specific antibody response in serum and Aβ-specific T-cell response (core only). Comparable Aβ-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments. Results: Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106-treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Aβ-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Aβ1–6 nor Aβ1–42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. Conclusions: No unexpected safety findings or Aβ-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Aβ-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD

Electrical “wiring” of viable Gluconobacter oxydans cells with a flexible osmium-redox polyelectrolyte

An application of a flexible polyvinylimidazole osmium functionalised polymer for efficient electrical wiring of whole Gluconobacter oxydans cells is described. The performance of the redox polymer as a mediator for intact bacterial cells was tested with glucose, ethanol and glycerol, typical substrates of the periplasmically localised PQQ-dependent membrane bound dehydrogenases. The efficiency of the electron transfer with the osmium redox polymer was compared with that of a soluble mediator (ferricyanide). Some basic bioelectrochemical characteristics, including Imax, Kmapp, inactivation constants and sensitivities were estimated for the mentioned substrates. The sensitivity profile for the tested substrates as well as the pH dependencies correspond well with the sensitivity profile for ferricyanide as soluble mediator. Significant stability differences for the substrates were found. Keywords: Gluconobacter, Mediated electron transfer, Pyrroloquinoline quinon

Improved selectivity of microbial biosensor using membrane coating. Application to the analysis of ethanol during fermentation

A ferricyanide mediated microbial biosensor for ethanol detection was prepared by surface modification of a glassy carbon electrode. The selectivity of the whole Gluconobacter oxydans cell biosensor for ethanol determination was greatly enhanced by the size exclusion effect of a cellulose acetate (CA) membrane. The use of a CA membrane increased the ethanol to glucose sensitivity ratio by a factor of 58.2 and even the ethanol to glycerol sensitivity ratio by a factor of 7.5 compared with the use of a dialysis membrane. The biosensor provides rapid and sensitive detection of ethanol with a limit of detection of 0.85 M (S/N=3). The selectivity of the biosensor toward alcohols was better compared to previously published enzyme biosensors based on alcohol oxidase or alcohol dehydrogenases. The biosensor was successfully used in an off-line monitoring of ethanol during batch fermentation by immobilized Saccharomyces cerevisiae cells with an initial glucose concentration of 200 g l−

A placebo-controlled study to evaluate the safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy

Background Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor (AR) gene. We assessed safety, tolerability, and preliminary efficacy of BVS857, an insulin like growth factor-1 (IGF-1) mimetic, in SBMA patients. SBMA patients have low IGF-1 levels, and studies of IGF-1 showed benefit in a transgenic model of SBMA. A study of BVS857 in healthy volunteers showed it to be well tolerated. Methods This study was double-blind, and placebo-controlled. Following a safety and tolerability evaluation with 8 SBMA patients, BVS857 was administered weekly for 12 weeks to 27 patients, with 2:1 drug to placebo randomization. Primary outcome measures included safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) by magnetic resonance imaging. Secondary and exploratory outcome measurements included pharmacokinetics, muscle strength and function, lean body mass by dual-energy x-ray absorptiometry scan, and pharmacodynamic biomarkers in blood and muscle biopsy samples. Findings BVS857 was generally safe with no serious adverse events. A significant difference in TMV was observed in the interventional arm versus placebo, with a decrease in TMV from baseline to week 13 in placebo but not in BVS857 treated patients. There was no difference in study measures of muscle strength or function. Immunogenicity was detected in 11 of 18 patients treated with BVS857, including cross-reacting antibodies with neutralizing capacity to endogenous IGF-1 in 5 patients. Interpretation TMV remained stable in BVS857 treated SBMA patients after 12 weeks of dosing. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Treatment with BVS857 for 12 weeks did not demonstrate benefit in SBMA. Additional studies may be needed to evaluate the efficacy of activating the IGF-1 pathway

Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial

Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043—a derivative of angiopoietin-like 3 (ANGPTL3)—as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin α5β1 on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial (NCT02491281; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial (NCT04864392) in patients with knee OA.ISSN:1078-8956ISSN:1546-170

Safety, tolerability, and preliminary e cacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

Background Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed bene t in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary e cacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. Methods In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a con rmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0\ub706 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the e ects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. Findings 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary e cacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No signi cant di erences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in ve patients. TMV decreased from baseline to day 85 in the placebo group (\u20133\ub74% [\u2013110 cm3]) but not in the BVS857 group (0% [2 cm3]). A signi cant di erence in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1\ub704 [90% CI 1\ub701\u20131\ub707]; p=0\ub702). There were no di erences between groups in measures of muscle strength and function. Interpretation TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the e cacy of activating the IGF-1 pathway in this disease. Funding Novartis Pharmaceuticals and the US National Institutes of Health

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy:a randomised, placebo-controlled trial

BackgroundSpinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy.MethodsIn this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932.Findings31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (-3·4% [-110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01-1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function.InterpretationTMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease.FundingNovartis Pharmaceuticals and the US National Institutes of Health