Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study.

Background: The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions.

Objective And Methods: This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24.

A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes.

Aim: To report the first study of temelimab, a monoclonal antibody neutralizing the pathogenic human endogenous retrovirus type W envelope, in patients with type 1 diabetes (T1D).

Materials And Methods: This double-blind, placebo-controlled, randomized clinical trial recruited adult patients with T1D within 4 years postdiagnosis and remaining C-peptide secretion. Sixty-four patients were randomized (2:1) to monthly temelimab 6 mg/kg or placebo during 24 weeks followed by a 24-week, open-label extension, during which all patients received temelimab.

A High-dose Pharmacokinetic Study of a New IgG4 Monoclonal Antibody Temelimab/GNbAC1 Antagonist of an Endogenous Retroviral Protein pHERV-W Env.

Purpose: Temelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS.

A new therapeutic approach for type 1 diabetes: Rationale for GNbAC1, an anti-HERV-W-Env monoclonal antibody.

We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV-W-Env). HERV-W-Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human β-islet cells.

A placebo randomized controlled study to test the efficacy and safety of GNbAC1, a monoclonal antibody for the treatment of multiple sclerosis - Rationale and design.

Background: GNbAC1, a humanized monoclonal antibody, is an innovative treatment currently in development for multiple sclerosis (MS) which, contrary to the immunomodulation/immunosuppressive mechanism of action of most of the MS drugs, targets specifically a protein of endogenous retroviral origin supposed to be critical in MS pathogenesis.

Methods: This trial is a randomized placebo controlled 4-arm study with the objective of demonstrating the efficacy of repeated doses of GNbAC1 on the cumulative number of T1 Gd-enhancing lesions measured from Week 12 to 24 in patients with relapsing remitting MS (RRMS). Two hundred sixty patients with RRMS are planned to be included.

Serum pharmacokinetics and cerebrospinal fluid concentration analysis of the new IgG4 monoclonal antibody GNbAC1 to treat multiple sclerosis: A Phase 1 study.

GNbAC1 is a humanized IgG4 monoclonal antibody antagonist of Mulitple Sclerosis Retrovirus Envelope (MSRV-Env), a protein that could play a critical role in multiple sclerosis. This randomized placebo-controlled dose-escalation study evaluated the safety and pharmacokinetics of GNbAC1 in 21 healthy volunteers after single intravenous infusion at doses of 6, 18 and 36 mg/kg. Lumbar punctures were performed at days 2, 15 or 29 to measure GNbAC1 concentrations in cerebrospinal fluid (CSF).

Treatment against human endogenous retrovirus: a possible personalized medicine approach for multiple sclerosis.

Human endogenous retroviruses (HERV) represent about 8 % of the human genome. Some of these genetic elements are expressed in pathological circumstances. A HERV protein, the multiple sclerosis-associated retrovirus (MSRV) envelope protein (MSRV-Env), is expressed in the blood and active brain lesions of multiple sclerosis (MS) patients.

A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients - a twelve month follow-up.

GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12months of a trial testing GNbAC1 in 10 MS patients at 2 and 6mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments.

Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein.

Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRV-Env) protein, an upstream factor in the pathophysiology of MS.

A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients.

Background: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation.

Objective: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments.

GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study.

Background: Human endogenous retrovirus (HERV) genes represent about 8% of the human genome. A member of the HERV family W, the Multiple Sclerosis-Associated Retrovirus (MSRV) gene, encodes an envelope protein (Env), which can activate a proinflammatory and autoimmune cascade through its interaction with Toll-like receptor 4. Due to its proinflammatory property and an inhibitory effect on oligodendrocyte precursor cell differentiation, the MSRV-Env protein could play a crucial role in the pathogeny of multiple sclerosis.

Triptorelin 6-month formulation in the management of patients with locally advanced and metastatic prostate cancer: an open-label, non-comparative, multicentre, phase III study.

Background And Objectives: Triptorelin 6-month formulation was developed to offer greater convenience to both patients and physicians by reducing the injection frequency. The efficacy, pharmacokinetics and safety of a new 6-month formulation of triptorelin were investigated over 12 months (48 weeks). The primary objective was to evaluate the formulation in achieving castrate serum testosterone levels (< or = 1.

The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naïve hepatitis C patients.

Unlabelled: The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-alpha2a (PEG IFN-alpha2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-alpha2a 180 microg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 microg/week PEG IFN-alpha2a. In patients with genotypes 1 and 4, the 600- and 1,000-mg combination treatments induced a continuous decay in viral load that reached -4.

Istaroxime, a first in class new chemical entity exhibiting SERCA-2 activation and Na-K-ATPase inhibition: a new promising treatment for acute heart failure syndromes?

Acute heart failure syndromes (AHFS) are associated with the rapid onset of heart failure (HF) signs and symptoms. Hospitalizations for AHFS continue to rise and are associated with significant mortality and morbidity. Several pharmacological agents are currently approved for the treatment of AHFS, but their use is associated with an increase in short-term mortality.

The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus.

Unlabelled: Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.

Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer.

Objective: To compare the efficacy of monthly administrations of the luteinizing hormone-releasing hormone agonists triptorelin pamoate and leuprolide acetate to induce and maintain castrate levels of serum testosterone in men with advanced prostate cancer.

Patients And Methods: Men with advanced prostate cancer were randomly assigned to receive triptorelin 3.75 mg or leuprolide 7.

Pharmacokinetics and pharmacodynamics of recombinant human chorionic gonadotrophin in healthy male and female volunteers.

The pharmacokinetics and pharmacodynamics of recombinant human chorionic gonadotrophin (rHCG) were investigated in three studies of healthy volunteers. After single intravenous doses of 25, 250 and 1000 microg, rHCG and urinary HCG (uHCG) showed linear pharmacokinetics described by a bi-exponential model, although the area under the curve (AUC) for uHCG was ~29% lower than for rHCG. After intramuscular or subcutaneous administration (absolute bioavailability, 40-50% for both), rHCG pharmacokinetics could be described by a first-order absorption, one-compartment model.

Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects.

Dehydroepiandrosterone (DHEA; 50 and 25 mg) and placebo tablets were orally administered daily to 24 healthy aging men and women (67.8 +/- 4.3 yr) for 8 days according to a balanced incomplete block design.

Down-regulation models and modeling of testosterone production induced by recombinant human choriogonadotropin.

Chorionic gonadotropin (CG) is a glycoprotein hormone, whose action is mediated by the luteinizing hormone/CG receptor. Testosterone concentrations from six pituitary-desensitized, healthy male volunteers were obtained after four different administrations of recombinant-human CG (rhCG). We present a modeling study to provide a possible explanation for the observations that increased exposure to rhCG induces higher and then lower testosterone concentrations and that marked rebound effects are observed at the end of repeated administration of rhCG.

Pharmacokinetic and pharmacodynamic interactions between recombinant human luteinizing hormone and recombinant human follicle-stimulating hormone.

Objective: To assess the pharmacokinetics of a recombinant human LH preparation and its pharmacokinetic and pharmacodynamic interactions with recombinant human follicle-stimulating hormone (FSH).

Design: Prospective, randomized cross-over study.

Setting: Phase I clinical research environment.

Clinical pharmacology of recombinant human luteinizing hormone: Part II. Bioavailability of recombinant human luteinizing hormone assessed with an immunoassay and an in vitro bioassay.

Objective: To assess the single-dose pharmacokinetics of a recombinant human LH preparation administered by the i.v., i.

Clinical pharmacology of recombinant human luteinizing hormone: Part I. Pharmacokinetics after intravenous administration to healthy female volunteers and comparison with urinary human luteinizing hormone.

Objective: To assess the pharmacokinetics after i.v. administration of a recombinant human LH and to compare them to those of a reference hMG preparation containing urinary human LH.

Pharmacokinetics of triptorelin after intravenous bolus administration in healthy males and in males with renal or hepatic insufficiency.

Aims: Triptorelin is a gonadotropin-releasing hormone (GnRH) analogue with enhanced affinity for GnRH receptors and a prolonged half-life due to its resistance to enzymatic degradation. The sustained-release formulation of this molecule is advantageous in conditions requiring chronic hormone suppression.

Methods: This was an open study to determine the pharmacokinetics of a single i.

Modeling a bivariate control system: LH and testosterone response to the GnRH antagonist antide.

A pharmacodynamic analysis of the input-response relationship between the gonadotropin-releasing hormone antagonist antide and luteinizing hormone (LH) and testosterone concentrations is presented. A control compartmental model is developed using pharmacokinetic and pharmacodynamic data from experiments in which different short intravenous antide infusions were given to healthy male volunteers. Because of the control interdependence between serum LH and testosterone a separation principle similar to one we have used previously to analyze physiological pharmacokinetic data is used for model exploration: testosterone and LH are first modeled separately, conditioning on the other observed response.

Comprehensive pharmacokinetics of urinary human follicle stimulating hormone in healthy female volunteers.

Purpose: The study determined the pharmacokinetics of urinary human follicle stimulating hormone (u-hFSH) in 12 down-regulated healthy female volunteers.

Methods: Following pituitary desensitization, baseline FSH serum levels were measured over a 24-hour period. Then each subject received, in random order, single doses of u-hFSH (Metrodin), 75 IU, 150 IU and 300 IU iv, and 150 IU im on four occasions separated by washout periods of one week.