Curtin F.,GeNeuro SA |
Hartung H.-P.,Heinrich Heine University Dusseldorf
Expert Review of Clinical Pharmacology
Multiple sclerosis (MS) is considered as an autoimmune disorder of the CNS with neuro-inflammatory and neurodegenerative components. We review here the innovative drugs recently registered and those in clinical development for MS. Immunomodulation has been the preferred therapeutic approach for MS since the first IFN-β was registered in the 1990s. Several immunomodulators are now available, which show a high efficacy in reducing the number of relapses in patients with the relapsing-remitting form of MS (RRMS). The high efficacy of most immunomodulators is, however, associated with substantial safety risks, notably concerning infections or cancers. Recently oral drugs have been approved for RRMS; however, biologics, and notably, monoclonal antibodies are still well represented in the development pipelines. An unmet medical need remains the treatment of the primary and secondary forms of MS or chronic progressive MS (CPMS). Half a dozen immunomodulators with proven efficacy in RRMS are now undergoing evaluation in Phase III trials in the CPMS indication. Neuroprotective drugs that prevent demyelination and/or improve remyelination would be interesting for CPMS, but these drugs are currently in the early development phase and their efficacy has not been demonstrated yet. © 2014 Informa UK Ltd. Source
Curtin F.,GeNeuro SA
Dialogues in Clinical Neuroscience
Randomized evidence from clinical trials and naturalistic evidence collected from pharmacoepidemiology and pharmacovigilance activities both contribute to the initial and continuous assessment of the benefits and risks of a drug, ie, the balance between therapeutic efficacy and safety risks. Benefit-risk assessment (BRA) mainly relies on a qualitative assessment of quantitative data. Current attempts to quantify BRA are reviewed and discussed, along with the expectations of regulatory authorities such as the Food and Drug Administration and the European Medicines Agency. No method provides a fully satisfactory solution regarding BRA, because it is difficult to reduce its multidimensional aspect to simple metrics, in a context where other therapeutic alternatives play a role. Consistency and transparency are key in this assessment, which is performed throughout the whole drug life cycle. BRA is mainly based on randomized clinical studies during clinical development, and it is continued and consolidated by naturalistic data once the drug is on the market. Source
Geneuro Sa | Date: 2014-03-21
A ligand includes each of the complementary-determining regions (CDRs) set forth in SEQ ID No. 1, SEQ ID No. 2, SEQ ID No. 3 SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6 or any sequence having either number of substituted aminoacids within said sequences as indicated in the following, from 0 to 3 in CDR1 (SEQ ID No.1), from 0 to 2 in CDR2 (SEQ ID No.2), from 0 to 2 in CDR3 (SEQ ID No.3), from 0 to 1 in CDR4 (SEQ ID No.4), from 0 to 4 in CDR5 (SEQ ID No.5), from 0 to 2 in CDR6 (SEQ ID No.6), or aminoacids substituted with other aminoacids having equivalent chemical functions and properties, within said sequences SEQ ID No. 1 to SEQ ID No. 6.
Curtin F.,GeNeuro SA |
Curtin F.,University of Geneva |
Vidal V.,GeNeuro SA |
Bernard C.,GeNeuro SA |
And 4 more authors.
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). GNbAC1 was well tolerated. Serum data show a dose-linear pharmacokinetics. A mean CSF/serum ratio of 0.12% was observed at Day 2, increasing to 0.39% at Day 15 and 0.42% at Day 29. Linear regression analysis shows a relationship between GNbAC1 CSF/serum ratio and albumin CSF/serum ratio and a relationship at the limit of statistical significance with the timing of CSF sampling. © 2016 Taylor & Francis Group, LLC. Source
Derfuss T.,University of Basel |
Curtin F.,GeNeuro SA |
Guebelin C.,University of Basel |
Bridel C.,University of Geneva |
And 13 more authors.
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. Methods: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. Results: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 2737 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. Conclusion: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period. © The Author(s), 2014. Source