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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

Multiple Sclerosis and Related Disorders, Volume 9, September 2016, Pages 95-100

Abstract

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. Three doses of GNbAC1 will be tested versus placebo: 6 mg/kg, 12  mg/kg and 18 mg/kg, administered intravenously, with 4-week administration intervals. The design is based on the classic 24-week placebo-controlled repeated brain MRI trial design (Period 1), with an extension of 24 weeks during which placebo patients will be re-randomized to one of the three doses of GNbAC1 to assess efficacy and safety of prolonged treatment of GNbAC1 (Period 2). The primary endpoint is the cumulative number of new Gadolinium enhanced T1 lesions measured using repeated brain magnetic resonance imaging (MRI) scans from Week 12 to 24; secondary endpoints, including additional MRI and clinical endpoints, will be assessed at the end of both Periods 1 and 2. Pharmacokinetics and biomarkers will be assessed in serum in all patients at several time points and also in cerebrospinal fluid in a subgroup of patients. To alleviate potential ethical concerns regarding placebo administration in MS, an early escape from trial will be implemented for patients with a worsening clinical condition during trial.

Conclusion

This dose-finding study should provide the first proof-of-concept of an innovative therapeutic approach for MS. The constraints of using a placebo group in RRMS patients while optimizing the trial power to evidence a new mechanism of action is discussed.

Highlights

  • GNbAC1 targets an endogenous retroviral protein involved in multiple sclerosis.
  • This protocol describes the first proof-of-concept trial for GNbAC1 monoclonal antibody.
  • Challenges to optimize study design while using a placebo in MS are discussed.

Keywords: Monoclonal antibody, Endogenous retrovirus, Phase II study, Magnetic resonance imaging, Relapsing remitting multiple sclerosis.

1. Introduction

GNbAC1 is a recombinant humanized IgG4 monoclonal antibody. Contrary to all drugs registered for multiple sclerosis (MS) with an immuno-modulating mechanism of action (MOA) (Curtin and Hartung, 2014), GNbAC1 selectively targets a protein called MSRV-Env, encoded by genes from the human endogenous retrovirus type W family (HERV-W), also named “Multiple Sclerosis associated Retrovirus” (MSRV), which may be a key pathological factor of MS (Perron et al, 1991 and Perron et al, 1997). Immunohistochemical analyses of post-mortem brain tissue from MS patients localizes the MSRV-Env protein to plaques showing that the level of protein expression was higher in active plaques than in older plaques (Perron et al., 2012, Mameli et al., 2007). Further the level of MSRV expression in the cerebrospinal fluid correlates with the clinical progression of MS (Sotgiu et al., 2010).

In MS, dysregulation of both innate and adaptive immune system is considered as the main triggering and/or exacerbating factor (Hemmer et al, 2015 Apr and Hohlfeld et al, 2016). MSRV-Env activates Toll-like receptor 4 (TLR4) and has a pro-inflammatory effect mediated through its interaction with TLR4 as shown in peripheral blood mononuclear cell (PBMC) cultures (Rolland et al., 2006). Moreover MSRV-Env can prevent the oligodendrocyte differentiation necessary for remyelination, also mediated by an interaction with TLR4 on oligodendrocyte precursor cells (OPC) (Kremer et al., 2013). Based on the ability of MSRV-Env to activate the innate immune system, and given its direct toxicity on OPCs, MSRV-Env appears to be a relevant therapeutic target for MS. It has been shown that GNbAC1 can minimize the activation of peripheral blood mononuclear cells, and block the toxic effect of MSRV-Env on OPC in vitro (Kremer et al., 2015a). In animal models of MS induced by MSRV, the treatment targeting MSRV-Env is efficacious on clinical endpoints and survival (Curtin et al, 2015a, Curtin et al, 2015b, and Perron et al, 2013), and remyelination can be observed in the brain of treated animals (Curtin et al, 2015a and Curtin et al, 2015b).

The anti-MSRV-Env monoclonal antibody GNbAC1 was assessed in a Phase I trial in 33 healthy subjects. The safety of GNbAC1 was good and linear pharmacokinetics were observed (Curtin et al., 2012). This was confirmed in another Phase I study with doses up to 36 mg/kg (Curtin et al., 2016). The penetration of the blood-brain barrier by GNbAC1 is in the expected range for monoclonal antibodies, with CSF/serum ratios from 0.2% to 0.4% (Curtin et al, 2012 and Curtin et al, 2016). GNbAC1 was also tested in 10 MS patients in a Phase IIa study: GNbAC1 safety appeared favorable and the PK was confirmed to be dose-linear (Derfuss et al., 2015b). The pharmacodynamic markers related to MSRV declined during treatment (Curtin et al, 2015b and Derfuss et al, 2015a) as it can be seen with interferon-ß and natalizumab (Mameli et al, 2008 and Arru et al, 2014). TLR4 activity in peripheral monocytes was re-normalizing during treatment (Zimmermann et al., 2015). These elements converge to support the further step in the clinical development of GNbAC1.

We report the rationale and study design for a phase IIb study testing GNbAC1 in patients with RRMS. This study will test monthly intravenous doses of 6, 12 and 18 mg/kg of GNbAC1 to determine GNbAC1 efficacy. Results will also assist in the selection of the optimal dose for Phase 3. The objective of this study should be reached with a trial design originally developed to assess immunomodulating drugs, in a clinical research context where placebo use is questioned.

2. Methods

2.1. Study design

This is a multicenter, double-blind, randomized, parallel-group phase-IIb study in 260 patients with RRMS receiving GNbAC1 or placebo during two periods: Period 1, which is placebo-controlled and is designed to assess the primary endpoint, and Period 2, an extension which includes only active treatment to assess the efficacy and safety of the prolonged treatment (See Fig. 1).

Fig. 1

Fig. 1

Study design, interventions and assessments.

 

2.1.1. Period 1 (Week 1–24)

In Period 1, all 260 patients will be randomized at a ratio 1:1:1:1–4 treatment groups: GNbAC1 6 mg/kg (65 patients), GNbAC1 12 mg/kg (65 patients), GNbAC1 18 mg/kg (65 patients), Placebo (65 patients), to receive six i.v. infusions of GNbAC1/placebo every 4 weeks.

2.1.2. Period 2 (Week 25–48)

Period 2 is an extension where up to 65 patients having remained in the placebo group at the end of Period 1 will be re-randomized at a ratio 1:1:1 to GNbAC1 6 mg/kg, GNbAC1 12 mg/kg, or GNbAC1 18 mg/kg to receive 6 doses of the active products at 4 week intervals. The patients already treated in the GNbAC1 groups during Period 1 will continue the active treatment (GNbAC1 6 mg/kg, 12 mg/kg, or 18 mg/kg) with another six doses at 4-week interval.

2.2. Use of placebo and early escape

Current EMA guidelines for the development of MS drugs support the use of a placebo arm in Phase II trials for 6 months, which ensures assay sensitivity (ICH E10, 2000). In this trial, the exposure to placebo will be limited to 24 weeks and the probability to receive the placebo will only be 0.25.

Placebo use is becoming controversial in MS even for clinical trials of short duration (Montalban, 2001). To improve the acceptability of a placebo-controlled design, an “early escape” is introduced, which allows to remove from the study a patient whose clinical status worsens and administer to him/her a registered treatment (ICH E10, 2000) whose choice will be determined by the investigator. Such an approach was applied in another MS Phase II trial (Kappos et al., 2014). Patients can go to this “early escape” path if during the placebo-controlled Period 1 they have more than one MS relapse; or an increase of >1 point in EDSS score confirmed after 3 months.

2.3. Study duration

The total duration is of 48 weeks. Usually, exploratory studies in RRMS last only 6 months, as efficacy can be observed on MRI endpoints already after a few weeks with immunomodulatory treatments (De Stefano et al., 2010). This study proposes a follow-up of 48 weeks to show the efficacy of the treatment beyond the usual six months and to explore a possible delayed treatment effect of GNbAC1 which might be encountered for two reasons. First, from a PK perspective, the plateau concentrations are reached after the 4th or 5th administrations (Derfuss et al, 2015a and Derfuss et al, 2015b), corresponding the pharmacokinetic equilibrium expected after five half-lives (Rowland and Tozer, 2010). Second, immunomodulatory immunoglobulins such as natalizumab or ocrelizumab show an efficacy already after two months (Kappos et al., 2011, Miller et al., 2003), but GNbAC1 MOA is different and the onset of full efficacy might take longer (Kremer et al, 2015b and Kremer et al, 2015a).

2.4. Setting

The study is planned to take place in 70 hospitals in 13 European countries (Bulgaria, Croatia, Czech Republic, Estonia, France, Germany, Hungary, Italy, Poland, Russia, Serbia, Spain, Ukraine).

2.5. Study population

The patient population will satisfy the following inclusion criteria: Male or female (if female: post-menopausal, surgically sterile, or using a highly effective method of contraception; if procreative male patients: using an effective method of contraception), between 18 and 55 years, suffering from RRMS according to the 2010 revised McDonald criteria (Polman et al., 2011) with ongoing disease activity characterized by at least one documented relapse during the last 12 months, or one Gd-enhancing T1 lesion at screening or evidenced on a brain MRI scan performed within the last 3 months, and an EDSS score <6.0. Patients will be excluded if they have a positive serology for hepatitis B or C or human immunodeficiency virus (HIV), positive pregnancy test, if they have abnormal liver tests and moderate to severe renal impairment or if they have been treated with DMT without of sufficient washout period.

A subgroup of 40 patients will be sampled for blood PK analysis, and another subgroup of 40 patients will also be asked for CSF sampling on a voluntary basis.

2.6. Investigational medicinal product and placebo

GNbAC1 is an IgG4 humanized monoclonal antibody targeting MSRV-Env (Curtin et al, 2015a and Curtin et al, 2015b). The placebo is GNbAC1 vehicle.

2.7. Procedures

Brain MRI scans for primary and secondary endpoints will be performed at baseline and at Weeks 12, 16, 20, 24, and 48 and will include the following assessments: T1 Gd-enhancing lesions, T2 lesions, T1-hypointense lesions, total volume of T1 Gd-enhancing lesions and T2 lesions; total brain volume and magnetic transfer ratio. Relapses will be recorded at each visit. Functional evaluations at baseline, Weeks 12, 24, 36 and 48, will include the Expanded Disability Status Scale (EDSS), and the Multiple Sclerosis Functional Composite (MSFC). The quality of life assessment will be performed at baseline, Week 24, and Week 48, including the MS-QoL54 and the numbers of hospitalizations and days off work over the whole study.

Adverse events will be reported at each visit. Vital signs and clinical safety laboratory and urinalysis will be performed at each visit. Cardiac safety will be assessed with 12-lead ECG at screening and at Week 48, and a Holter ECG at the 1st (baseline) and 6th administration (week 20).

Blood PK sampling will be performed in all patient at 4 times points; (D85, 169, 253, 337). Optional additional samples will be taken in selected study centers in a subgroup of 40 patients (subgroup 1) at the following time points: pre-dose and at 2 h 10 min and 6 h after the start of the IMP infusion on Days 1 and 309 and before each infusion in between and 4 weeks after the last infusion. Serum concentrations of GNbAC1, the accumulation factor and the time to reach steady-state will be determined.

CSF PK assessments will be performed in a second subgroup of around 40 patients (subgroup 2). In these patients, CSF samples will be obtained before the start of IMP infusion at one to three of the following time points: at screening, at Day 169, and Day 337. CSF concentrations of GNbAC1 will be determined.

MSRV markers and neurofilaments (NFL) will be assessed in blood or serum before GNbAC1 infusion on Days 1, 85, 169, 253, and 337. MSRV markers and possibly also biomarkers of CNS disease activity such asmyelin basic protein (MBP) and NFL will be measured in CSF at screening and possibly also on Day 169, and/or Day 337 in the subgroup of patients undergoing CSF assessment.

The assessment of anti-GNbAC1 antibodies will be on the following days: before GNbAC1 infusion on Days 1, 85, 169, 253, and 337.

2.8. Endpoints

The primary efficacy endpoint will be the cumulative number of T1 Gd-enhancing lesions measured from Week 12 to 24 by MRI. Secondary endpoints will include the cumulative number of combined unique active (CUA) lesions computed from Week 16 to 24; the number of T1 Gd-enhancing lesions at Week 24; the cumulative number of new T2 lesions from Week 16 to 24, the cumulative number of new T1-hypointense lesions from Week 16 to 24; the percentages of patients free of T1 Gd-enhancing lesions over 24 weeks and at Week 24, of patients free of new T2 lesions over 24 weeks and at Week 24 and of patients free of new T1 hypointense lesions over 24 weeks and at Week 24; the change from baseline in total volume of T1 Gd-enhancing lesions at Week 24; the change from baseline in total volume of T2 lesions at Week 24; the percentage of brain volume change from baseline to Week 24; the magnetization transfer ratio (MTR) change from baseline to Week 24; the annualized MS relapse rate from baseline to W24, the percentage of patients free of radiological and clinical disease activity. Specific scales and questionnaires will also be described such as: EDSS changes from baseline to Week 24, MSFC changes from baseline to Week 24, the MS-QoL54 changes from baseline to Week 24. At 48 weeks the following endpoints will be assessed: the cumulative number of T1 Gd-enhancing lesions measured from Week 24 to 48, the cumulative number of T1 Gd-enhancing lesions measured from Week 16 to 48, the cumulative number of T2 lesions measured from Week 24 to 48, the cumulative number of T2 lesions measured from Week 16 to 48, the percentage of brain volume change from baseline to Week 48, the annualized MS relapse rate from W24 to W48 and from baseline to W48; the percentage of patients free of radiological and clinical disease activity. The following scales and questionnaires will be answered: EDSS changes vs. baseline to Week 48, the MSFC changes from baseline to Week 48, the MS-QoL54 changes from baseline to Week 48, the percentage of confirmed disability (EDSS change ≥1.5 points for patient with EDSS=0; EDSS change≥+1.0 point for patients with EDSS>0 and <5.5; or EDSS change≥+0.5 points for patients with EDSS≥5.5 confirmed after 3 months) from baseline to Week 48.

During the whole study the following endpoints will be assessed: MSRV markers and neurofilament in blood or serum and anti-GNbAC1 antibodies in serum; GNbAC1 serum concentrations in a subgroup of n=40 patients and CSF levels of GNbAC1, MSRV markers and possibly other relevant biomarkers (for example neurofilament and MBP) in another subgroup of around 40 patients.

2.9. Statistical analysis

2.9.1. Primary endpoint analysis

The primary endpoint observed with each dose of GNbAC1 will be compared to placebo in the per protocol set (defined as patients who had an assessable MRI at both baseline and Week 24, did not miss two consecutive post-baseline MRIs between Week 12 and 24), using a Negative Binomial Generalized Linear Model (Sormani et al., 1999) with adjustment for covariates (e.g. the absence or presence of baseline Gd-enhancing T1 lesions).

2.9.2. Multiplicity adjustment

Overall Type I error rate will be controlled at 2.5% using a fixed sequence of testing procedure (Wiens, 2003). Each test in the sequence shown in Fig. 2 will be tested at 2.5% until a null hypothesis cannot be rejected; the remaining null hypotheses could then not be rejected.

Fig. 2

Fig. 2

Sequence of statistical tests for the primary endpoint analysis.

 

2.9.3. Analysis of other endpoints

The tolerability/safety and PK data will be evaluated descriptively.

2.9.4. Stratified analysis

Subgroups defined by baseline MSRV-Env mRNA blood levels will be used to perform exploratory stratified analyses on the efficacy and safety endpoints to identify whether MSRV-Env mRNA may be predictive of efficacy/safety responses with the objective of developing potential companion diagnostic (Curtin et al, 2015a and Curtin et al, 2015b).

2.9.5. Period 2 analysis
  • 1) Patients with placebo in Period 1 and GNbAC1 in Period 2.

Efficacy assessment will be performed in patients who switched from placebo to GNbAc1 in Period 2. MRI endpoints assessed from week 24 to week 48 and MRI endpoints measured during Period 1 will be described as well as annualized relapse rate from week 24 to week 48 and annualized relapse rate assessed during Period 1.

  • 2) Patients with GNbAC1 in Period 1 and GNbAC1 in Period 2.

Assessment of efficacy maintenance will be performed in Period 2 in the subgroup of patients who received treatment with GNbAC1 over the two Periods. MRI endpoints assessed from week 24 to week 48 and MRI endpoints measured during Period 1 will be described as well as annualized relapse rate from week 24 to week 48 and annualized relapse rate assessed during Period 1.

2.10. Sample size calculation

The cumulative number of Gd-enhancing T1 lesions is assumed to be a variable following a negative binomial distribution (Sormani et al., 1999). Sample size and power calculations were carried out for the primary endpoint of T1 Gd-enhancing lesions using a simulation-based method (10,000 simulation runs) and formulas by Keene et al. (2007):

FORMULA:

stripin: si0001.gif

where µ1 and µ2 are the mean of cumulative number of lesions in placebo and active treatment arms respectively, k is the dispersion parameter (shape) and zx are the values of the standardised normal distribution at x. The following assumptions were used: Expected mean of cumulative number of lesions in the placebo group: 4; common dispersion parameter (shape): 0.5; expected treatment effect of 60% reduction in the highest active dose group corresponding to a cumulative number of lesions of 1.6. With number of 61 evaluable patients per treatment group, using the NBGLM and a 2.5% type I error rate (one-sided p-value), the expected power is 90% as was confirmed by simulation studies (see Table 1). Assuming an attrition rate of 5% over 6 months, 64.2, rounded to 65, patients per treatment group are necessary and thus 260 patients overall will be included in the study.

Table 1

Simulations of power according to sample size treatment effect and dispersion parameter.

 

Dispersion No. of lesions in placebo group No. of lesions in active arm (high dose) Magnitude of treatment effect (%) Sample size/arm Keene's formula (1-sided alpha=0,025, power 90%) Power by simulation (1-sided alpha=0,025) (%)
Primary endpoint: Gad+T1
0.3 4 2 50 162.2 90.32
0.4 4 2 50 125.75 90.29
0.5 4 2 50 103.88 90.02
0.6 4 2 50 89.3 90.04
0.65 4 2 50 83.69 90.21
0.3 4 1.6 60 94.38 90.22
0.4 4 1.6 60 73.52 90.27
0.5 4 1.6 60 61.01 90.24
0.6 4 1.6 60 52.67 90.24
0.65 4 1.6 60 49.46 90.45

3. Discussion

GNbAC1 is a monoclonal antibody with an innovative MOA: by targeting MSRV-Env expressed on microglial cells and on circulating lymphocytes, it is expected that GNbAC1 will inhibit the inflammatory and myelinotoxic actions of MSRV-Env which are considered as key pathogenic factors of the disease. This Phase IIb study will be performed in RRMS patients as the study design in this indication is well established (Lublin, 2005; EMA, 2015). The major challenge of this study is to assess a new MOA with a trial design respecting ethical and regulatory constraints.

The use of an active comparator was explored. As GNbAC1 has a MOA totally different from the current treatments, the effect size of GNbAC1 versus an active treatment is difficult to anticipate. In case of a treatment effect of small relative magnitude during the first months of treatment, a very large sample size would be required which could jeopardize the performance of such a trial. The latter remark is also true if GNbAC1 would be used as an add-on treatment (Lublin, 2005). Moreover, the safety data would be confounded by the safety profile of the other treatment at a stage where assessing the safety profile of GNbAC1 is necessary.

MS experts have established guidelines for the use of placebo in clinical trials at the light of numerous available established effective therapies in MS (Polman et al., 2008), proposing that “proof of concept studies may be ethical under the provision of the Declaration of Helsinki that requires sound methodologic scientific reasons for placebo-controlled trials when established effective therapy is available”, highlighting the need for very clear explanations in the informed consent of patients (Polman et al., 2008). The Declaration of Helsinki states that one cannot test an experimental drug against the best proven intervention when “[…] for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention, and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.” (World Medical Association, 2013). Indeed there is no clear evidence that a short term deprivation of an effective therapy, i.e. during 6 months, leads to longer term differences in outcomes (Polman et al., 2008), an observation supported by long term observation suggesting dissociation between inflammatory relapses and the risk of progression toward secondary progressive MS (Scalfari et al., 2013). Long-term benefit of MS treatments such as interferon-β in patients treated earlier compared to patients having been under placebo prior to entering extension studies was observed in some studies (Bermel et al., 2010; Goodin et al, 2012 Apr 24 and Rudick et al, 2005) but was not clear in others (Ebers et al, 2010 and Kappos et al, 2006 Sep 26). The treatment delays were between 2 and 5 years in these different studies, which is considerably longer than the 6 months proposed in this study. The new 2015 EMA guidelines states: “The preferred approach would be a development showing superiority versus placebo or an active comparator (i.e. first line disease modifying treatments (DMT) like β-interferons, glatiramer acetate)”. However, the absence of a placebo arm in a clinical trial might be problematic as “apparent efficacy could be explained by the regression to the mean, a placebo effect, as well as by the natural course of the disease” (European Medicine Agency, 2015). As Temple and Ellenberg (2000) point out, historically based assumptions of assay sensitivity are often not possible, so that for many types of effective drugs, studies of apparently adequate size and design do not regularly distinguish drugs from placebo. To increase the acceptability of the present study, the probability to receive a placebo is reduced to 25% and we propose to introduce an “early escape” possibility if a patient gets worse, as suggested by ICH E10 (2000). This allows starting a treatment at the choice of the investigator when the patient has left the study. The setting of this study with monthly visits and proposed worsening endpoints is fully appropriate to implement this measure.

Period 2 might also provide information to explore a possible delayed onset of action of GNbAC1: Should the product's effects on MSRV need a couple of months before translating into radiologically and clinically meaningful results, a difference might be observed in efficacy parameters during period 1 versus period 2 in patients having received GNbAC1 during both study periods. However, because of the absence of a placebo group in period 2, several factors could influence these results, such as the natural evolution of the disease or regression to the mean (Stellmann et al, 2015 and Zhao et al, 2008), therefore this analysis will be exploratory.

The objective of this study is to demonstrate the efficacy of GNbAC1 on an MRI endpoint in RRMS, and to determine the dose with the highest benefit-risk ratio. In addition to placebo, three active arms are included in a parallel design following the recommendation of the ICH E4, (1994) guideline. The statistical method of analysis is based on the closure principle and protects against the inflation of the familywise type I error rate. This analytical method of successive testing does not proscribe selecting a dose for further development based on risk-benefit criteria.

If the proof of concept of the first anti-MSRV-Env treatment is established, this could completely change the way MS is addressed. In addition to the promising results in RRMS, the capacity of GNbAC1 to act on the remyelination process (Curtin et al, 2015a and Curtin et al, 2015b; Kremer et al, 2015b and Kremer et al, 2015a) could make it particularly interesting for treatment of progressive forms of MS. Addressing the unknown of a new MOA in MS with the constraints of minimizing the exposure to placebo and optimizing the trial design makes such a study challenging, but the design presented here should allow to perform this study in the most efficient and ethical fashion.

Ethics approvals

The study has been approved so far by the central ethics committees and regulatory authorities of Spain, Hungary, Ukraine, Poland and Estonia.

Competing interests

FC, HP, RG, VV are employees of Geneuro SA. HMS, MLA, EL are employees of Servier. HPH has received honoraria from GeNeuro SA and Servier.

Funding

The sponsor of this study is GeNeuro SA.

Authors' contributions

FC wrote the manuscript. FC, HP, RG, HMS, HPH designed the study. VV and MLAI wrote the protocol of the study. EL designed the statistical analysis. All authors have read and approved the final manuscript.

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Footnotes

a GeNeuro SA, Chemin des Aulx 18, CH 1228 Plan-les-Ouates, Geneva, Switzerland

b Division of Clinical Pharmacology and Toxicology, Rue Perret-Gentil, University of Geneva, Geneva, Switzerland

c Department of Pharmacology, University of Pretoria, Pretoria, South Africa

d International Institute of Research Servier, 50 rue Carnot, F-92100 Suresnes, France

e Department of Neurology and Center of Neuropsychiatry, Heinrich Heine Universtität, Düsseldorf, Germany

Corresponding author at: GeNeuro SA, 18 Chemin des Aulx, CH-1228 Plan-les-Ouates, Switzerland.


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