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Schoumacher M.,Institute Of Recherches Servier Idrs | Burbridge M.,Institute Of Recherches Internationales Servier Iris
Current Oncology Reports | Year: 2017

A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired. A principal role of AXL appears to be in sustaining a mesenchymal phenotype, itself a major mechanism of resistance to diverse anticancer therapies. Both AXL and MER play a role in the repression of the innate immune response which may also limit response to treatment. Small molecule and antibody inhibitors of AXL and MER have recently been described, and some of these have already entered clinical trials. The optimal design of treatment strategies to maximize the clinical benefit of these AXL and MER targeting agents are discussed in relation to the different cancer types and the types of resistance encountered. One of the major challenges to successful development of these therapies will be the application of robust predictive biomarkers for clear-cut patient stratification. © 2017, The Author(s).


Kennedy S.H.,University of Toronto | Gimenez-Montesinos N.,Institute Of Recherches Internationales Servier Iris | Belaidi C.,Institute Of Recherches Internationales Servier Iris | Christian de B.,Institute Of Recherches Internationales Servier Iris
European Neuropsychopharmacology | Year: 2014

A randomised placebo-controlled "dose relation study" was conducted in 549 patients who met the criteria for major depressive disorder, to evaluate the efficacy and safety of three doses regimens of agomelatine during 6 weeks: low fixed dosage (10mg/day, n=133), fixed dosage (25mg/day, n=138) and a flexible dosage with up-titration in case of insufficient improvement at week 2 (25-50mg/day, n=137). At last post-baseline assessment, there were significant and incremental placebo-agomelatine differences on mean HAM-D17 total scores in favour of each agomelatine dose regimen (2.46±0.76 points, p=0.001 at 10mg; 4.71+0.75 points, p<0.0001 at 25mg and 4.92±0.76 points, p<0.0001 at 25-50mg) with statistically significant differences between 25mg and 25-50mg dose regimens compared to the 10mg dose. The response rate according to HAM-D17 was significantly higher in patients taking agomelatine than those taking placebo (difference of 16.1% at 10mg p=0.005; 25.9% and 27.4% respectively at 25mg and 25-50mg, p<0.0001). The benefit of agomelatine was demonstrated in the subgroup of severely depressed patients in the 25mg and 25-50mg/day regimens. Consistent clinical response according to CGI variables and better social functioning were found in patients receiving agomelatine. All dose regimens of agomelatine were well tolerated and no unexpected adverse event was reported. This study provides evidence of a dose effect for agomelatine between 10mg and the therapeutic dose regimen of agomelatine 25-50mg: the efficacy of the higher dose regimens being more efficacious than the lowest (10mg) daily dose. The data support a definitive statement regarding the utility of 25mg as the threshold dose for initiating agomelatine in depressed patients. © 2014 Elsevier B.V. and ECNP.


Swedberg K.,Gothenburg University | Komajda M.,University Pierre and Marie Curie | Bohm M.,Universitatskliniken des Saarlandes | Borer J.S.,New York University | And 4 more authors.
The Lancet | Year: 2010

Background Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure. Methods Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35 or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7·5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960. Findings 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22·9 (IQR 18-28) months. 793 (24) patients in the ivabradine group and 937 (29) of those taking placebo had a primary endpoint event (HR 0·82, 95 CI 0·75-0·90, p<0·0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 [21] placebo vs 514 [16] ivabradine; HR 0·74, 0·66-0·83; p<0·0001) and deaths due to heart failure (151 [5] vs 113 [3]; HR 0·74, 0·58-0·94, p=0·014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0·025). 150 (5) of ivabradine patients had symptomatic bradycardia compared with 32 (1) of the placebo group (p<0·0001). Visual side-effects (phosphenes) were reported by 89 (3) of patients on ivabradine and 17 (1) on placebo (p<0·0001). Interpretation Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder. Funding Servier, France. © 2010 Elsevier Ltd.


Corruble E.,University Paris - Sud | De Bodinat C.,Institute Of Recherches Internationales Servier Iris | Belaidi C.,Institute Of Recherches Internationales Servier Iris | Goodwin G.M.,University of Oxford
International Journal of Neuropsychopharmacology | Year: 2013

Abstract In the present randomized, controlled, double-blind trial (12 wk treatment plus double-blind extension for 12 wk), 25-50 mg/d agomelatine (n = 164) and 10-20 mg/d escitalopram (n = 160) were compared for short- and long-term efficacy, subjective sleep and tolerability. The effects of these drugs on emotional experiences were also compared in patients having completed the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants (agomelatine: n = 25; escitalopram: n = 20). Agomelatine and escitalopram similarly improved depressive symptoms, with clinically relevant score changes over 12 and 24 wk and notable percentage of remitters (week 12: 60.9 and 54.4%; week 24: 69.6 and 63.1% respectively). Over the 12 and 24-wk treatment periods, the 'global satisfaction on sleep' scores increased in both treatment groups and did not differ between groups. Satisfaction with sleep-wake quality was high in both groups; the 'wellness feeling on waking' was more improved with agomelatine than with escitalopram (p = 0.02). In patients with pronounced sleep complaints, quality of sleep and feeling on waking were significantly more improved with agomelatine than with escitalopram (p = 0.016 and p = 0.009, respectively). Emotional blunting was less frequent on agomelatine than on escitalopram. Indeed, 28% of patients on agomelatine vs. 60% on escitalopram felt that their emotions lacked intensity and 16% of patients on agomelatine vs. 53% on escitalopram felt that things that they cared about before illness did not seem important any more (p = 0.024). The tolerability profile of agomelatine was found to be superior to that of escitalopram and the incidence of patients with at least one emergent adverse event leading to treatment discontinuation was lower in the agomelatine group than in the escitalopram group (5.5 vs. 10.6%). The findings suggest that agomelatine displays additional long-term clinical benefits on sleep-wake quality and emotional experiences over escitalopram in the management of depression. © CINP 2013.


Stein D.J.,University of Cape Town | Ahokas A.,Mehilainen Clinic | Marquez M.S.,Teaching and Research in Neuroscience | Haschl C.,Prague Psychiatric Center | And 5 more authors.
Journal of Clinical Psychiatry | Year: 2014

Background: Agomelatine was efficacious in reducing symptoms in a short-term placebo-controlled trial in generalized anxiety disorder (GAD) and in preventing relapse in a longer term placebo-controlled study. An additional short-term placebo-controlled study is required by regulatory agencies to confirm the efficacy of agomelatine in GAD. Method: This 12-week, placebo-controlled, double-blind, randomized, parallel group, international, multicenter study was designed to confirm the efficacy of agomelatine 25 50 mg/d in the treatment of patients with a primary D5M-IV- TR diagnosis of GAD. The primary outcome measure was the Hamilton Anxiety Rating Scale (HARS) total score. Assay sensitivity was evaluated by including an escitalopram (10 20 mg/d) group. Settings:The study was undertaken in 45 clinical centers in Argentina, Czech Republic, Finland, South Korea, Poland, Russia, and Slovakia from April 2010 to July 2011. Results: One hundred thirty-nine outpatients were included in the agomelatine group, 131 in the placebo group, and 142 in the escitalopram group. Agomelatine significantly reduced mean (SD) HARS total score (agomelatine-placebo difference: 4.71 [1.03], P< .0001) and had significant effects on secondary outcome measures, including psychic and somatic HARS subscales, response rate (estimate [standard error]) (agomelatine-placebo difference: 27.4% [5.9%], P <.0001), remission on the HARS (agomelatine-placebo difference: 16.8% [5.4%], P .002), Clinical Global Impressions- Severity of Illness scale (CGI-S) (P <.001), functional impairment (P< .0001), and sleep quality (P< .001). Findings were confirmed in the subset of more severely ill patients (HARS total score >25 with or without CGI S >5 at baseline). Agomelatine was well tolerated by patients, with no more adverse events than placebo. Escitalopram was similarly efficacious but was accompanied by a higher incidence of adverse events compared to placebo. Conclusions: In clinical practice, agomelatine has at least similar efficacy to that of escitalopram for the short-term treatment of GAD and is well tolerated. Trial Registration: Control led-Tria ls.com identifier: 1SRCTN03554974. © 2014 Physicians Postgraduate Press, Inc.


Bousser M.-G.,University Paris Diderot | Amarenco P.,University Paris Diderot | Chamorro A.,University of Barcelona | Fisher M.,University of Massachusetts Medical School | And 7 more authors.
The Lancet | Year: 2011

Background: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke or other cardiovascular events. We compared the selective thromboxane-prostaglandin receptor antagonist terutroban with aspirin in the prevention of cerebral and cardiovascular ischaemic events in patients with a recent non-cardioembolic cerebral ischaemic event. Methods: This randomised, double-blind, parallel-group trial was undertaken in 802 centres in 46 countries. Patients who had an ischaemic stroke in the previous 3 months or a TIA in the previous 8 days were randomly allocated with a central interactive response system to 30 mg per day terutroban or 100 mg per day aspirin. Patients and investigators were masked to treatment allocation. The primary efficacy endpoint was a composite of fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (excluding haemorrhagic death). We planned a sequential statistical analysis of non-inferiority (margin 1·05) followed by analysis of superiority. Analysis was by intention to treat. The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee. This study is registered, number ISRCTN66157730. Findings: 9562 patients were assigned to terutroban (9556 analysed) and 9558 to aspirin (9544 analysed); mean follow-up was 28·3 months (SD 7·7). The primary endpoint occurred in 1091 (11%) patients receiving terutroban and 1062 (11%) receiving aspirin (hazard ratio [HR] 1·02, 95% CI 0·94-1·12). There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints. We recorded some increase in minor bleedings with terutroban compared with aspirin (1147 [12%] vs 1045 [11%]; HR 1·11, 95% CI 1·02-1·21), but no significant differences in other safety endpoints. Interpretation: The trial did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban. In a worldwide perspective, aspirin remains the gold standard antiplatelet drug for secondary stroke prevention in view of its efficacy, tolerance, and cost. Funding: Servier, France. © 2011 Elsevier Ltd.


Bohm M.,Universitatsklinikum des Saarlandes | Swedberg K.,Gothenburg University | Komajda M.,University Pierre and Marie Curie | Borer J.S.,New York University | And 4 more authors.
The Lancet | Year: 2010

Background Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population. Methods We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly. Findings In the placebo group, patients with the highest heart rates (≥87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio [HR] 2·34, 95 CI 1·84-2·98, p<0·0001). Risk of primary composite endpoint events increased by 3 with every beat increase from baseline heart rate and 16 for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4, 95 CI 15·3-19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85-1·06, p=0·352). Interpretation Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure. Funding Servier, France. © 2010 Elsevier Ltd.


Stein D.J.,UCT | Ahokas A.,Mehilainen Clinic | Albarran C.,Institute Of Recherches Internationales Servier Iris | Olivier V.,Institute Of Recherches Internationales Servier Iris | Allgulander C.,Karolinska Institutet
Journal of Clinical Psychiatry | Year: 2012

Objective: This study evaluated the efficacy and tolerability of agomelatine in the prevention of relapse in patients with generalized anxiety disorder (GAD). Method: Patients with GAD (Hamilton Anxiety Rating Scale [HARS] ≥ 22, with items 1 and 2 ≥ 2, item 1 + 2 ≥ 5; Montgomery-Asberg Depression Rating Scale [MADRS] ≤ 16; and < 20% decrease in HARS total score between screening and baseline) who responded to a 16-week course of agomelatine 25-50 mg/d treatment were randomly assigned to receive continuation treatment with agomelatine (n = 113) or placebo (n = 114) for 26 weeks. The main outcome measure was time to relapse during this maintenance period. The estimated risk of relapse was calculated using the Kaplan-Meier method, and groups were compared using a log-rank test stratified for country. The study was undertaken in 31 clinical centers in Canada, Denmark, Estonia, Finland, Hungary, and Sweden from November 2007 to September 2009. Results: During the 6-month maintenance period, the proportion of patients that relapsed during the double-blind period in the agomelatine group (22 patients, 19.5%) was lower than in the placebo group (35 patients, 30.7%). The risk of relapse over time was significantly lower for patients who continued treatment than for those switched to placebo (P = .046, log-rank test stratified for country). Agomelatine was also superior to placebo in preventing relapse in the subset of more severe patients with baseline HARS total score ≥ 25 and CGI-S score ≥ 5. The tolerability of agomelatine was good throughout the study, and there were no differences in discontinuation symptoms after withdrawal of agomelatine in comparison to maintenance on agomelatine. Conclusions: The present study extends the positive findings of an earlier short-term study of agomelatine in GAD, demonstrating that agomelatine is effective and well-tolerated in the longer-term treatment of this chronic disorder. Trial Registration: www.isrctn.org identifier: ISRCTN38094599. © Copyright 2012 Physicians Postgraduate Press, Inc.


Heun R.,Derby City General Hospital | Ahokas A.,Mehilainen Clinic | Boyer P.,University of Ottawa | Boyer P.,University Paris Diderot | And 3 more authors.
Journal of Clinical Psychiatry | Year: 2013

Objective: The present placebo-controlled study evaluated the efficacy, tolerability, and safety of 8-week treatment with agomelatine (25-50 mg/d by mouth) in elderly patients with major depressive disorder (MDD). Method: Elderly outpatients aged ≥ 65 years with a primary diagnosis of moderate to severe episode of recurrent MDD (DSM-IV-TR) were recruited in 27 clinical centers in Argentina, Finland, Mexico, Portugal, and Romania from November 2009 to October 2011. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS17) total score. Results: A total of 222 elderly patients entered the study (151 in the agomelatine group, 71 in the placebo group), including 69 patients aged 75 years and older. Agomelatine improved depressive symptoms in the elderly population, as evaluated by the HDRS17 total score, in terms of last postbaseline value (agomelatine-placebo difference: mean estimate [standard error] = 2.67 [1.06] points; P = .013) and response to treatment (agomelatine, 59.5%; placebo, 38.6%; P = .004). The agomelatine-placebo difference according to the Clinical Global Impressions-Severity of Illness scale (CGI-S) score was 0.48 (0.19). The agomelatine-placebo difference (estimate [standard error]) for remission on the HDRS17 was 6.9% (4.7%) and did not achieve statistical significance (P = .179, post hoc analysis). Clinically relevant effects of agomelatine were confirmed on all end points in the subset of severely depressed patients (HDRS17 total score ≥ 25 and CGI-S score ≥ 5 at baseline). Agomelatine was well tolerated by patients, with only minimal distinctions from placebo. Conclusions: The present study provides the first evidence that an 8-week treatment with agomelatine 25-50 mg/d efficiently relieves depressive symptoms and is well tolerated in elderly depressed patients older than 65 years. © 2013 Copyright Physicians Postgraduate Press, Inc.


Canet E.,Institute Of Recherches Internationales Servier Iris | Lerebours G.,Institute Of Recherches Internationales Servier Iris | Vilaine J.-P.,Institute Of Recherches Servier Idrs
Annals of the New York Academy of Sciences | Year: 2011

The link between elevated heart rate and cardiovascular events is established in healthy individuals and in patients with cardiovascular disease. The new agent, ivabradine, specifically and selectively inhibits the I f current, with the sole action of heart rate reduction, with no impact on any other cardiac parameters. The benefits of "pure" heart rate reduction with ivabradine have been the focus of one of the largest clinical development programs ever performed, involving >20,000 individuals. Ivabradine has anti-ischemic and antianginal efficacy in monotherapy, as well as in combination with other antianginals, such as beta-blockers, and is safe and well tolerated. Two major morbidity-mortality trials, BEAUTIFUL and SHIFT, showed that heart rate reduction with ivabradine dramatically improves prognosis in patients with coronary artery disease and left ventricular dysfunction, symptomatic angina, or chronic heart failure. The development of ivabradine represents a clear innovation in the management of cardiovascular disease. © 2011 New York Academy of Sciences.

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