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Beprana, INN-Naproxcinod EMA/657046/2011 Committee for Medicinal Products for Human Use (CHMP) Assessment report Beprana naproxcinod Procedure No.: EMEA/H/C/002159/ Applicant: NicOX S.A Note Rapporteurs’ day 180 joint assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. This should be read in conjunction with the “Question and Answer” document on the withdrawal of the application: the Assessment Report may not include all available information on the product if the CHMP assessment of the latest submitted information was still ongoing at the time of the withdrawal of the application. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged. TABLE OF CONTENTS EXECUTIVE SUMMARY ................................................................................. 6 Problem statement ................................................................................................... 6 About the product..................................................................................................... 6 The development programme/Compliance with CHMP Guidance/Scientific Advice............ 7 General comments on compliance with GMP, GLP, GCP .................................................. 7 Type of application and other comments on the submitted dossier ................................... 8 SCIENTIFIC OVERVIEW AND DISCUSSION .................................................. 9 Quality aspects ........................................................................................................ 9 Non clinical aspects................................................................................................. 10 Clinical aspects ...................................................................................................... 32 ORPHAN MEDICINAL PRODUCTS ............................................................... 77 BENEFIT RISK ASSESSMENT ...................................................................... 77 Conclusions ........................................................................................................... 82 Beprana Assessment report Page 2/82 LIST OF ABBREVIATIONS Abbreviation Definition ABPM ambulatory blood pressure monitoring ACE angiotensin converting enzyme ACR American College of Rheumatology ADP adenosine diphosphate AE adverse event ALT alanine aminotransferase ANCOVA analysis of covariance ANOVA analysis of variance APTC Anti-Platelet Trialists’ Collaboration ARB angiotensin II receptor blockers ASA acetylsalicylic acid AST aspartate aminotransferase AT1 angiotensin II type 1 AUC area under the curve BD butanediol BDMN butanediol mononitrate bid bis in die (twice daily) BLQ below the limit of quantification BP blood pressure CAD coronary artery disease CCB calcium channel blockers cGMP cyclic guanosine 3,5-monophosphate CHD coronary heart disease CHMP The Committee for Medicinal Products for Human Use CI confidence interval CINOD cyclooxygenase-inhibiting nitric oxide donator CL clearance CNS central nervous system COX(-2) cyclooxygenase (2) CrCl creatinine clearance CSR clinical study report CV cardiovascular CYP1A2 isoenzyme 1A2 of cytochrome P450 DBP diastolic blood pressure DSMB Data Safety Monitoring Board ECG electrocardiogram EMEA European Medicines Agency F fraction of drug absorbed FDA Food and Drug Administration fu unbound fraction GCP good clinical practice GFR glomerular filtration rate GI gastrointestinal Beprana Assessment report Page 3/82 Abbreviation Definition GHB gammahydroxybutyric acid GST glutathione s-transferase HR hazard ratio IMP investigational medicinal product INR international normalisation ratio ISE Integrated Summary of Efficacy ISMB Independent Safety Monitoring Board ITT intent-to-treat IV intravenous Kow octanol-water partition coefficient LOCF last observation carried forward LS least squares MedDRA Medical Dictionary for Regulatory Activities MI myocardial infarction mLOCF modified last observation carried forward MAA Marketing Authorisation Application MHRA The Medicines and Healthcare products Regulatory Agency MPA Medical Products Agency MPID mean pain intensity difference NNH numbers needed to harm NO nitric oxide NSAID nonsteroidal anti-inflammatory drug OA osteoarthritis OARSI Osteoarthritis Research Society International OBPM office blood pressure monitoring PABA para-aminobenzoic acid PCS potentially clinically significant PD pharmacodynamic PK pharmacokinetic PP per-protocol PPI proton pump inhibitor PT preferred term PUB Peptic ulcer bleeding qd quaque die (once daily) time between the beginning of the QRS complex and end of the T- QT wave RAB renin angiotensin blockers RMP risk management plan SAE serious adverse event SAP statistical analysis plan SBP systolic blood pressure SC subcutaneous SD standard deviation SEDDS self-emulsifying drug delivery system SEM standard error of the mean Beprana Assessment report Page 4/82 Abbreviation Definition SmPC summary of product characteristics SMQ standard MedDRA query SOC system organ class tid ter in die (three times daily) TxB2 thromboxane B2 VAS visual analogue scale vs versus Vu volume of distribution WOCF worst observation carried forward WOMAC™ Western Ontario and McMaster Universities Osteoarthritis Index Beprana Assessment report Page 5/82 EXECUTIVE SUMMARY Problem statement Osteoarthritis (OA) is a degenerative joint disease associated with pain, swelling, and loss of motion. The histopathologic hallmark is cartilage degeneration which may lead to exposed bone, deformation of the joint, growth of bone spurs, and fragments of cartilage floating in the synovial fluid, which in turn cause more pain and reduced mobility. In Europe the prevalence varies by country ranging from approximately 6% in Greece to 13% in Norway. Therefore, up to 35 million people in Europe would be affected by OA, with an incidence increasing with age. It is estimated that half of adults aged ≥ 65 years report symptoms of OA and the disease is more common in women than in men over the age of 50 years. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage inflammation and pain, and the majority of NSAID prescriptions are for the treatment of OA and other arthritic conditions. However a number of side-effects are associated with NSAID use. These include an increased risk of cardiovascular events, which are considered to be associated with the effects of NSAIDs on blood pressure (BP) and effects on the gastric mucosa, which can lead to peptic erosions and ulcers. There is a high prevalence of co-morbidities in the general OA population such as cardiovascular, gastrointestinal and metabolic diseases. Therefore, for both the patient and the physician, it is of utmost importance to balance the benefit of medication for pain relief and the risk associated with gastro-intestinal (GI) and cardiovascular safety. About the product Naproxcinod (also referred to as AR-P900758XX, AZD3582, or HCT 3012 in early studies) is a cyclooxygenase (COX)-inhibiting nitric oxide (NO) donator, which has been designed to provide at least the same anti-inflammatory and analgesic efficacy as marketed NSAIDs with an improved safety profile, particularly with respect to GI safety and BP. This profile was intended to be achieved by designing a molecule with two active moieties both of which are released following rapid, systemic metabolic cleavage. The first moiety comprises the long established NSAID naproxen to provide relief from the signs and symptoms of OA; the second is a novel NO-donating moiety the release of which is designed to counteract the detrimental effects of naproxen on BP and to some extent provide protection from the effects of naproxen on the GI tract and other organs. NO possesses marked vascular smooth- muscle relaxant properties through activation of soluble guanylyl cyclase and consequent formation of cyclic guanosine monophosphate (cGMP). Figure 1: Structure of Naproxcinod Ester bond O + O N O O O O naproxen Nitric oxide donating moiety (BDMN) Since naproxen and the NO donating moiety are combined in this product via the ester bound in a 1:1 relation no dose titration of NO was possible and the applicant does not address this issue in the dossier. In this context it is not expected that both therapeutic principles, naproxen and NO, are dosed Beprana Assessment report Page 6/82 in their appropriate therapeutic range. More justification is needed why both compounds were not combined as single entities thus allowing titration of pharmacological effects of naproxen on one hand and the NO donator on the other hand. The development programme/Compliance with CHMP Guidance/Scientific Advice CHMP scientific advice was sought by AstraZeneca and finalised in April 2003 (EMEA/CPMP/SAWP/2254/03). Subsequently, in September 2006, additional scientific advice was sought by NicOx, following return of the product from Astra Zeneca, and a revision of the clinical development program (EMEA/CHMP/SAWP/359675/2006). Scientific advice was also obtained from the MHRA in 2002 and 2006 (AZD3582: AstraZeneca-MCA Scientific Advice) and (046/HCT 3012: NicOx- MHRA Scientific Advice) and from the Medical Products Agency (MPA) in 2006 (HCT 3012: NicOx-MPA Scientific Advice). The overall clinical development programme consisted of 34 clinical studies and
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