Australian Public Assessment Report for Agomelatine Proprietary Product Name: Valdoxan Submission No: PM-2009-00483-3-1 Sponsor: Servier Laboratories (Australia) Pty Ltd October 2010 Contents I. Introduction to Product Submission........................................................................3 Submission Details.................................................................................................................. 3 Product Background................................................................................................................ 3 Regulatory Status .................................................................................................................... 5 Product Information ................................................................................................................ 5 II. Quality Findings.........................................................................................................6 Introduction............................................................................................................................. 6 Drug Product........................................................................................................................... 6 Bioavailability......................................................................................................................... 6 Quality Summary and Conclusions......................................................................................... 7 III. Nonclinical Findings ..................................................................................................7 Introduction............................................................................................................................. 7 Nonclinical Summary and Conclusions.................................................................................. 7 IV. Clinical Findings ........................................................................................................8 Introduction............................................................................................................................. 8 Pharmacodynamics ............................................................................................................... 10 Pharmacokinetics .................................................................................................................. 17 Efficacy ................................................................................................................................. 18 Safety .................................................................................................................................... 27 Clinical Summary and Conclusions...................................................................................... 53 Supplementary Data..............................................................................................................54 V. Pharmacovigilance Findings...................................................................................63 Risk Management Plan ......................................................................................................... 63 VI. Overall Conclusion and Risk/Benefit Assessment ................................................64 Quality................................................................................................................................... 64 Nonclinical............................................................................................................................ 64 Clinical.................................................................................................................................. 65 Risk-Benefit Analysis ...........................................................................................................71 Outcome................................................................................................................................ 72 Attachment 1. Product Information..............................................................................72 AusPAR Valdoxan Agomelatine Servier Laboratories (Australia) Pty Ltd PM-2009-00483-3-3 Final 21 October 2010 Page 2 of 87 I. Introduction to Product Submission Submission Details Type of Submission New Chemical Entity Decision: Approved Date of Decision: 5 August 2010 Active ingredient(s): Agomelatine Product Name(s): Valdoxan Sponsor’s Name and Servier Laboratories (Australia) Pty Ltd Address: 8 Cato Street Hawthorn Vic 3122 Dose form(s): Film-coated tablet Strength(s): 25 mg Container(s): Blister pack Pack size(s): 28 or 56 Approved Therapeutic use: The treatment of major depression in adults including prevention of relapse. Route(s) of administration: Oral Dosage: The recommended dose is 25 mg once daily taken in the evening. The dose may be increased to 50 mg once daily (2 x 25 mg) taken in the evening if clinically indicated. ARTG Number (s) 159712 Product Background The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has noted that Major Depressive Disorder (MDD) is reported to be the most common mood disorder.1 Depressive disorders tend to be chronic and both relapse and recurrence are seen frequently. The presumed mechanism of action of the majority of antidepressants in the treatment of MDD is thought to be via inhibition of neuronal reuptake of monoamines (mainly serotonin and noradrenaline), with a resultant increase in monoamine neurotransmission in the central nervous system (CNS). The agomelatine molecule possesses a new pharmacological mechanism of action, which combines its melatonin MT1 and MT2 agonist properties with a serotonin 5-HT2C antagonist effect. The 5-HT2C receptors is considered a relevant target with regard to antidepressant therapy, as several currently used antidepressant drugs have 5-HT2C receptor antagonist properties (for example, mianserin and mirtazapine). There have been two submissions to register agomelatine in Australia. 1 Valdoxan EPAR: http://www.ema.europa.eu/humandocs/PDFs/EPAR/valdoxan/H-915-en6.pdf - accessed 18 June 2010. AusPAR Valdoxan Agomelatine Servier Laboratories (Australia) Pty Ltd PM-2009-00483-3-3 Final 21 October 2010 Page 3 of 87 First Submission (2005): At the first presentation in April 2007 the Australian Drug Evaluation Committee (ADEC) recommended rejection on the grounds of lack of established clinical efficacy, concerns regarding safety especially at the higher 50 mg dose (inadequate patient exposure) and inadequate pharmacokinetic characterisation of agomelatine. Further, the Committee supported its Pharmaceutical Subcommittee (PSC) recommendation that the sponsor should provide an absolute bioavailability study to support registration. Second Submission (2009): That first submission was withdrawn and the current submission, containing new efficacy and safety data, was considered by the ADEC in August 2009. Deficiencies were again identified by the ADEC which again recommended rejection of the submission on the grounds that efficacy and safety have not been adequately demonstrated. In making this recommendation, the ADEC agreed that the results of the newly presented relapse study (041) showed that in patients who satisfactorily respond to agomelatine 25 mg or 50 mg daily, continuation of agomelatine at the same dose prolongs that response. This contrasts to the previously presented relapse study (021) which failed to show a significant benefit for agomelatine over placebo. However, ADEC considered that there continued to be a lack of robust evidence to support the efficacy of agomelatine in treating episodes of depression. ADEC noted that the new submission includes an active controlled study of agomelatine against sertraline. However, the primary aim of this study was to compare the time course of effect of the two treatments on various circadian/sleep- wake cycles, and evidence of antidepressant efficacy was a secondary outcome only. Thus, although the antidepressant effect of agomelatine was statistically superior (but of uncertain clinical relevance) to that of sertraline in terms of the HAM-D total score and CGI severity of illness score during the first 6 weeks of treatment, these data can only be regarded as supportive of efficacy.2,3 The second submission initially provided no new placebo-controlled data regarding the short-term efficacy of agomelatine. Accordingly, the situation with respect to use in this setting is largely unchanged from the original submission, that is, the efficacy of agomelatine is statistically significantly superior to placebo but this difference is of doubtful clinical relevance. Overall therefore, acceptance of efficacy rests primarily on the one of the two relapse prevention studies which demonstrated a benefit for agomelatine over placebo. This was not considered by ADEC to be an adequate basis upon which to recommend registration. In terms of safety, the committee continued to be concerned about the lack of adequate patient exposure at the higher 50 mg dose, with data provided for only 44 patients treated with 50 mg daily for more than 12 months. Also of concern was the incidence of potentially clinically significant transaminase elevations (>3 x the upper limit of normal [ULN]). There is some evidence that the incidence of this adverse event is increased at higher agomelatine doses. The committee noted that the maximal plasma concentration (Cmax) and the area under the plasma concentration time curve from time zero to infinity