Christian Wolf

Lycalis sprl

We assessed the safety and efficacy of orally administered CC chemokine receptor 1 (CCR1) antagonist in 105 patients with relapsing/remitting MS (RRMS) in a 16-week, randomized, double-blind, placebo-controlled trial. The primary endpoint was the cumulative number of newly active lesions on serial MRI scans. Other MRI, immunologic, and clinical out...

There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in CSF are being used in clinical practice. One of the most critical factors in CSF biomarker research is the inadequate powering of studies because of the lack of sufficient samples that can be obtained...

Importance The patents for the first approved treatments for relapsing-remitting multiple sclerosis are expiring, creating the opportunity to develop generic alternatives.Objective To evaluate in the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study whether generic glatiramer acetate (hereafter generic drug) is eq...

Background: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5modulator, on disability progression in patients with SPMS. Methods: This event-driven and exposure-...

To evaluate the efficacy and tolerability of sulthiame (STM) as monotherapy in children with benign childhood epilepsy with centrotemporal spikes (BECTS). Sixty-six BECTS patients entered a 6-month double-blind trial and were randomized to receive either STM (5 mg/kg/day) or a placebo. All patients had had two or more seizures during the 6 months p...

Background and objectives: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to furthe...

Introduction: As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) have started to emerge. FO-DMTs have the potential to reduce health- care costs. However, unintended nocebo effects may occur when switching from reference product (RP) to FO-DMT due to adverse expectations of people with MS (PwMS...

Introduction: Vidofludimus calcium (VidoCa, formerly called IMU-838) is a 2nd generation, highly selective, orally available DHODH inhibitor which does not show off-target effects on kinases and provides a safety and tolerability profile similar to placebo. More than 1100 subjects have been exposed to vidoflu- dimus, to date. Currently, Phase 3 stu...

Introduction: As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) have started to emerge. FO-DMTs have the potential to reduce health- care costs. However, unintended nocebo effects may occur when switching from reference product (RP) to FO-DMT due to adverse expectations of people with MS (PwMS...

Background As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) become available at reduced cost. Concerns exist that cheaper FO-DMTs are used simply to reduce healthcare costs. However, the well-being of people with MS should take priority. Objectives To identify best practices for FO-DMT devel...

Objective: Inhibition of dihydroorotate dehydrogenase suppresses magnetic resonance imaging brain lesions and disease activity in multiple sclerosis but has limiting tolerability. We assessed the safety and efficacy of vidofludimus calcium, a novel, selective dihydroorotate dehydrogenase inhibitor, in patients with relapsing-remitting multiple scl...

Earlier diagnosis, access to disease-modifying therapies (DMTs), and improved supportive care have favorably altered the disease course of multiple sclerosis (MS), leading to an improvement in long-term outcomes for people with MS (PwMS). This success has changed the medical characteristics of the population seen in MS clinics. Comorbidities and th...

Objective: To investigate the effects of siponimod on cognitive processing speed (CPS) in secondary progressive (SP) multiple sclerosis (MS) patients, by means of a pre-defined exploratory, and post-hoc analysis of the EXPAND study, a randomized controlled trial (RCT) comparing siponimod and placebo. Methods: EXPAND was a double-blind, placebo-c...

Background In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses. Objective To distinguish siponimod’s direct effects on disability progression from those on relapses in the EXPAND phase 3 trial. Methods Three estimands, one based on principal stratum and two on hypothetical scen...

Background: In chronic diseases such as multiple sclerosis requiring lifelong treatment, studies on long-term outcomes are important. Objective: To assess disability and magnetic resonance imaging-related outcomes in relapsing multiple sclerosis patients from a Phase 2 study of fingolimod 10 or more years after randomization and to compare outco...

Glatiramer acetate is indicated for the treatment of patients with relapsing forms of multiple sclerosis (RMS). In 2016, an alternative to the originator product was approved in the EU through the hybrid procedure regulatory pathway. This paper reviews the scientifically rigorous and multifaceted program undertaken to demonstrate the equivalence of...

Cognitive impairment affects 50%–70% of multiple sclerosis (MS) patients and is more severe in secondary progressive MS (SPMS) than in relapsing–remitting MS Decreased cognitive processing speed (CPS) constitutes a core, underlying deficit in MS patients. The Symbol Digit Modalities Test (SDMT) is the recommended screening test gold standard measur...

Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized,...

Objective: To present safety and tolerability results of the randomized, double-blind, placebo-controlled, Phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). Background: Siponimod, a selective sphingosine 1-phosphate (S1P) receptor-1/-5 modulator with peripheral and central e...

Objective: To present the efficacy results of the randomized, double-blind, placebo-controlled, phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). Background: Siponimod, a selective sphingosine 1-phosphate receptor-1 and -5 modulator with peripheral and central effects was in...

Background: Open-label 15-month follow-up of the double-blind, placebo-controlled Glatiramer Acetate clinical Trial to assess Equivalence with Copaxone(®) (GATE) trial. Objective: To evaluate efficacy, safety, and tolerability of prolonged generic glatiramer acetate (GTR) treatment and to evaluate efficacy, safety, and tolerability of switching...

Background: There is high unmet need for treatments that delay disability progression in secondary progressive multiple sclerosis (SPMS). Siponimod (BAF312) is an orally active selective modulator of the sphingosine-1-phosphate receptor subtypes 1 and 5. EXPAND is the largest randomised controlled study in SPMS to date. Objective: EXPAND is a phas...

Background: Although the short-term controlled trials with the mGluR5 antagonist AFQ056 were not efficacious in adult and adolescent patients with fragile X syndrome (FXS), researchers were hopeful that improvements could be seen in long-term open-label studies. Methods: Adults with FXS who underwent a controlled trial of AFQ056 were offered enrol...

BACKGROUND: GTR (Synthon) is the first generic glatiramer acetate with a demonstrated equivalent efficacy and safety profile to branded glatiramer acetate (GA, Copaxone®, Teva). Because local injection site reactions (LISRs) are common adverse reactions for GA, these were further investigated. OBJECTIVE: To evaluate local tolerability following tre...

Background: Generic alternatives to the currently approved therapies for relapsing-remitting multiple sclerosis (RRMS) are needed. Because glatiramer acetate (COP, Teva) is a complex polypeptide mixture, precluding pharmacokinetic comparison, a generic version should demonstrate equivalence in efficacy and safety. Objectives: The GATE trial aimed t...

Effective therapies reducing visual impairment resulting from acute demyelinating optic neuritis (ADON) are an important unmet medical need. The ADONIS (Fingolimod in acute demyelinating optic neuritIs) study will investigate the effects of fingolimod in ADON both on an anatomical and clinical level and will advance the knowledge about structural a...

Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS). Investigate the effect of CDP323, an oral α-integrin inhibitor, on lymphocyte biomarkers in RMS. Seventy-one RMS subjects aged 18-65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatme...

CONSORT Checklist. (DOC)

Trial Protocol. (PDF)

Evaluating the long term benefit of therapy in multiple sclerosis (MS) is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established. In a patient cohort from the pivotal interferon β-1b trial, the value of clinical...

This paper intends to show that the use of a single-center, early-phase trial setting with patients has benefits over the widely accepted multicenter approach.

There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in cerebrospinal fluid (CSF) are being used in clinical practice. Anti-aquaporin-4 antibodies in serum are currently useful for the diagnosis of neuromyelitis optica (NMO), but we could expect novel CSF...

Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16 y, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. The 372 trial patients were randomly assigned to placebo (n=123), IFNB-1b 50 microg (n=125) or IFNB-1b 250 microg (n=124) subcutane...

Objective: To obtain proof of concept and dosing information for CDP323, an orally bioavailable α4 integrin inhibitior, in the treatment of relapsing forms of multiple sclerosis (RMS). Background: CDP323, a small molecule inhibiting the binding of α4 integrins to their ligands, has an acceptable pre-clinical toxicology profile and did show efficac...

Zusammenfassung Die Erforschung von Biomarkern in Körperflüssigkeiten bei neurodegenerativen und neuroinflammatorischen Erkrankungen blickt auf eine langjährige Geschichte zurück. Dennoch werden nur wenige Liquor cerebrospinalis (Liquor)-Biomarker in der klinischen Praxis verwendet. Einer der problematischen Faktoren in der Liquorbiomarker-Forschun...

Die Erforschung von Biomarkern in Körperflüssigkeiten bei neurodegenerativen und neuroinflammatorischen Erkrankungen blickt auf eine langjährige Geschichte zurück. Dennoch werden nur wenige Liquor cerebrospinalis (Liquor)-Biomarker in der klinischen Praxis verwendet. Einer der problematischen Faktoren in der Liquorbiomarker-Forschung ist die einges...

This article describes the design of and difficulties inherent in the execution of a long-term, observational trial that sought to assess the validity of short-term measures of multiple sclerosis (MS) (eg, relapse rate, inflammatory lesions) for long-term disease outcomes. In the original double-blind, placebo-controlled interferon (IFN)-p1b study,...

To evaluate the effects of sulthiame (Ospolot; STM) monotherapy compared with placebo on the EEG in children with benign childhood epilepsy with centrotemporal spikes (BECTS). Sixty-six patients (aged 3-11 years) entered a 6-month double-blind trial and were randomized to either STM (n = 31) or placebo (n = 35). Clinical data and general results ha...

An open pilot study with the dopamine agonist alpha-dihydroergocryptine (DHEC) was conducted in 16 patients with idiopathic restless legs syndrome (RLS) over a period of 5 weeks. Following a drug-free interval of 1 week, the patients were treated with daily doses of 10 to 40 mg DHEC. As compared to baseline values, treatment led to a statistically...

The effect of the sulfonamide derivative sulthiame (Ospolot) on voltage-operated sodium channels was investigated in acutely isolated neurons from the guinea pig hippocampus using the whole-cell patch-clamp technique. Sulthiame in a concentration of 10 microg/ml reduced the inactivating sodium currents without affecting potassium currents. The effe...

A 1-year double-blind study of carbamazeplne (CBZ; Timonil® retard) versus lithium for prophylaxis of bipolar affeclive disorders was carried out in 168 patients in 7 Hungarian psychiatric units. Purpose was to clarify the value of CBZ's efficacy in comparison to lithium as available studies have confiicting results and methodological problems. Maj...

The choice of parenteral anticonvulsants is limited. So far, only parenteralia of the older anticonvulsants have been available. The recent introduction of a valproate formulation for intravenous use extends the therapeutic armentarium. This paper reviews the available pre-clinical and clinical information with regard to pharmacokinetics, tolerabil...

A 1-year double-blind study of slow-release carbamazepine (Timonil® retard) versus lithium for the prophylaxis of bipolar affective disorders was carried out in 168 patients in six Budapest psychiatric units from 1994 to 1997. Its purpose was to clarify the value of carbamazepine's (CBZ) efficacy in comparison to lithium as the available studies ha...

The replacement of oral valproate with dose-equivalent therapy with Orfiril® injection solution at steady state was investigated in 12 healthy volunteers. Both treatment mo-dalities were administered twice daily. Treatment with Orfiril® enteric coated tablets was bioequivalent in comparison with Orfiril® injection solution with regard to the extent...

In a randomised, double-blind study the efficacy and tolerability of slow-release carbamazepine versus clomethiazole were investigated in 28 patients during therapy for alcoholic predelirium. No statistically significant differences were observed with regard to duration and severity of withdrawal. Unwanted effects of carbamazepine therapy included...

A three-month post-marketing surveillance of 286 patients with partial forms of epilepsy investigated the efficacy and tolerability of a slow-release carbamazepine formulation (Timonil® retard) when transferring from other antiepileptic agents and from conventional carbamazepine formulations.167 patients were transferred from conventional tablets t...

In a randomised, double blind study the efficacy and tolerability of slow-release carbamazepine (Timonil 150 retard) versus clomethiazole were investigated in 28 patients during drug therapy for alcoholic predelirium. No statistically significant differences between the two drugs were observed with regard to duration and severity of withdrawal symp...