Uptravi, INN- selexipag

1 30 Churchill Place Canary Wharf London E14 5EU United Kingdom An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged. 01 April 2016 EMA/272184/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report uptravi International non-proprietary name: selexipag Procedure No. EMEA/H/C/003774/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. uptravi ( selexipag ) Assessment Report Page 2/117 Table of contents 1. Background information on the procedure.

2 6 Submission of the dossier .. 6 Steps taken for the assessment of the product .. 7 2. Scientific discussion .. 8 Introduction .. 8 Quality aspects .. 8 Introduction .. 8 Active Substance .. 8 Finished Medicinal Product .. 11 Discussion on chemical, pharmaceutical and biological aspects .. 13 Conclusions on the chemical, pharmaceutical and biological aspects .. 13 Recommendation(s) for future quality development .. 13 Non-clinical aspects .. 14 Introduction .. 14 Pharmacology .. 14 Pharmacokinetics .. 18 Toxicology .. 21 Ecotoxicity/environmental risk assessment .. 29 Discussion on non-clinical aspects .. 29 Conclusion on non-clinical aspects .. 31 Clinical aspects.

3 31 Introduction .. 31 Pharmacokinetics .. 32 Pharmacodynamics .. 38 Discussion on clinical pharmacology .. 40 Conclusions on clinical pharmacology .. 43 Clinical efficacy .. 44 Dose response studies .. 44 Main study .. 46 Discussion on clinical efficacy .. 70 Conclusions on clinical efficacy .. 74 Clinical safety .. 75 Discussion on clinical safety .. 88 Conclusions on clinical safety .. 90 Risk Management Plan .. 90 Pharmacovigilance .. 102 Product information .. 102 User consultation .. 102 Additional monitoring .. 102 uptravi ( selexipag ) Assessment Report Page 3/117 3. Benefit-Risk Balance .. 103 4. Recommendations .. 112 uptravi ( selexipag )

4 Assessment Report Page 4/117 List of abbreviations 6 MWD 6-minute walk distance 6 MWT 6-minute walk test ADME Absorption, distribution, metabolism, excretion AS Active substance AUC Area under plasma concentration-time curve AUC Area under plasma concentration-time curve during a dose interval AUC0- Area under plasma concentration-time curve from 0 to infinity AUC0-t Area under plasma concentration-time curve from 0 to t h Twice a day CAMPHOR Cambridge Pulmonary Hypertension Outcome Review CEC Critical Event Committee CES carboxylesterase CFU Colony Forming Units CHD congenital heart disease CI Confidence interval Cmax Maximum plasma concentration Cmax,ss Maximum plasma concentration at steady-state CTD Connective tissue disease CTEPH Chronic thromboembolic pulmonary hypertension Ctrough Plasma concentration at the end of one dose interval Ctrough,ss Plasma concentration at the end of one dose interval at steady-state Cu/C concentration of free (unbound) to total plasma concentration CV Coefficient of variation CVb Inter-subject coefficient of variation CVw Intra-subject coefficient of variation DMC Data Monitoring Committee (also referred to as DSMB, Data Safety Monitoring Board)

5 DSMB Data Safety Monitoring Board eGFR estimated glomerular filtration rate EOS End of study ERA Endothelin receptor antagonist GC Gas Chromatography GCP Good Clinical Practice GLP good laboratory practice GMP Good Manufacturing Practice HCl Hydrochloric acid HIV Human immunodeficiency virus HPAH Heritable pulmonary arterial hypertension (formerly familial PAH) HPLC(/DAD) High performance liquid chromatography (/Diode Array Detector) ICH International Conference on Harmonisation IMP Investigational medicinal product IPAH Idiopathic pulmonary arterial hypertension IPC In-process control IP receptor Prostacyclin receptor, PGI2 receptor IR Infrared LC-MS/MS Liquid chromatography coupled to tandem mass spectrometry LVEDP Left ventricular end diastolic pressure uptravi ( selexipag ) Assessment Report Page 5/117 MACE Major adverse cardiovascular events MAP Mean arterial pressure mPAP Mean pulmonary arterial pressure mRAP Mean right atrial pressure NMR Nuclear Magnetic Resonance NS304 selexipag NT pro-BNP N-terminal pro-brain natriuretic peptide NYAH New York Heart Association PDE5 Phosphodiesterase type-5 Ph.

6 Eur. European Pharmacopoeia OL Open-label PK Pharmacokinetic(s) PD Pharmacodynamic(s) RH Relative humidity QC Quality control SAD Single-ascending dose SD Standard deviation SE standard error SRFI severe renal function impairment t Time t Terminal elimination half-life tmax Time to reach maximum plasma concentration tmax,ss Time to reach maximum plasma concentration at steady-state UGT uridine-glucuronosyltransferase USP United States Pharmacopoeia UV Ultraviolet WHO World Health Organization uptravi ( selexipag ) Assessment Report Page 6/117 1. Background information on the procedure Submission of the dossier The applicant Actelion Registration Ltd. submitted on 1 December 2014 an application for Marketing Authorisation to the European Medicines Agency (EMA) for uptravi , through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004.

7 The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 25 April 2013. uptravi , was designated as an orphan medicinal product EU/3/05/316 on 26 August 2005. uptravi was designated as an orphan medicinal product in the following indication: Treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Following the CHMP positive opinion at the time of the review of the orphan designation by the Committee on Orphan Medicinal Products (COMP), this product was withdrawn from the Community Register of designated orphan medicinal products on 17 February 2016 upon request of the sponsor. The applicant applied for the following indication: uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH; WHO Group I) in adult patients with WHO functional class (FC) II IV.

8 uptravi is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy. Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with congenital heart disease with repaired shunts (see section ). The legal basis for this application refers to: Article of Directive 2001/83/EC - complete and independent application. The applicant indicated that selexipag was considered to be a new active substance. The application submitted is composed of administrative information, complete quality data, non-clinical and clinical data based on applicants own tests and studies and/or bibliographic literature substituting/supporting certain test(s) or study(ies).

9 Information on Paediatric requirements Pursuant to Article 7of Regulation (EC) No 1901/2006, the application included an EMA Decision(s) PIP P/0154/2013 on the agreement of a paediatric investigation plan (PIP). At the time of submission of the application, the PIP P/0154/2013 was not yet completed as some measures were deferred. Information relating to orphan market exclusivity Similarity Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the applicant did submit a critical report addressing the possible similarity with authorised orphan medicinal products. uptravi ( selexipag ) Assessment Report Page 7/117 Applicant s request(s) for consideration New active Substance status The applicant requested the active substance selexipag contained in the above medicinal product to be considered as a new active substance in itself, as the applicant claims that it is not a constituent of a product previously authorised within the Union.

10 Protocol Assistance The applicant received Protocol Assistance from the CHMP on 24 February 2006 and 26 April 2007. The Protocol Assistance pertained to non-clinical and clinical aspects of the dossier. Licensing status The product was not licensed in any country at the time of submission of the application. Steps taken for the assessment of the product The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur: Martina Weise Co-Rapporteur: Concepcion Prieto Yerro The application was received by the EMA on 1 December 2014. The procedure started on 24 December 2014. The Rapporteur's first Assessment Report was circulated to all CHMP members on 16 March 2015. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 25 March 2015.