1. Analysis of Global New Molecular Entities 2012 The beginning of a new wave? Analysis of Global New Molecular Entities 2012 The beginning of a new wave? Hélène Kaplon*, Lucie Lindner*, Marine Monfourny*, Julie Mouton*, Pauline Roussel*, Violette Launoy*, Teddy Saladin*, Julie Trolle*, Rebecca Deprez and André Tartar, * Students at the Faculty of Pharmacy of Lille, France Faculté de pharmacie 3, Rue du professeur Laguesse 59000 LilleFrance FDA : www.nature.com/reviews/drugdisc EUROPE : http://www.ema.europa.eu/ema/ JAPON : http://www.mhlw.go.jp/english/ The list of NMEs published every year by the FDA is considered by many observers as the most reliable parameter to evaluate the evolution of pharmaceutical research productivity. However, it gives a biased picture. For the purpose of this study, we have analyzed the 45 “global New Molecular Entities” (gNME) - corresponding to 34 gNCE and 11 gNME - that have appeared on the world market in 2012. A global New Molecular Entity being defined as any active ingredient obtained by synthetic (NCE) or biological (NBE) route which is approved worldwide for the first time by one of the three major agencies: EMA for Europe, FDA for the USA and MHLW for Japan. 2012 Analysis Background 27 NMEs 4 orphan drugs 14 % 45 NMEs 17 orphan drugs 38 % 2011 2012 Bedaquiline (Sirturo®)Ivacaftor (Kalydeco®)Trastuzumab emtansine (Kadcyla®)Dapagliflozine (Forxiga®)Cobicistat MultiDrugResistance TuberculosisCystic FibrosisMetastatic breast cancer HER 2 +Diabetes Mellitus Cytochrome P450 3A4 inhibitor HIV-1 infection This diarylquinoline compound discovered by whole-cell screening inhibits selectively mycobacterial ATP synthase. It is the first anti-tuberculosis drug approved since 40 years. Ivacaftor is indicated for the treatment of cystic fibrosis among patients with the G551D mutation. This mutation causes the deregulation of the opening of the CFTR channel. As a potentiator, Ivacaftor increases the time of CFTR protein activation and opening at cell surface. Anti-HER2 antibody conjugated to a derivative of maytansine-1 (DM-1), a potent cytotoxic agent. By binding to HER2, it forms a complex that is internalized in the lysosome, where the thioether linkage is cleaved to release DM-1 which inhibits the polymerization of microtubules. Dapagliflozin inhibits the subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 98% of glucose reabsorption in the kidney. This compound derived from phlorizin whose structure has been modified to provide a bioavailable and selective compound. Cobicistat is a pharmacokinetic booster used in a combo to treat HIV-1. By inhibiting selectively CYP3A4 it prevents the rapidt metabolisation of elvitegravir, an integrase inhibitor. Its structure is derived from ritonavir in which the hydroxy group responsible for protease inhibition has been deleted. Highlights Orphan drugs among gNMEs Therapeutics Areas (2011 versus 2012) gNCE and gNBE While between 2000 and 2011, the number of global New Chemical Entities (gNCE) has remained almost stable. It has increased sharply in 2012 with 34 gNCE compared to 20 in 2011 and 17 in 2010. By comparison, only 11 global New Biological Entities (gNBE) have reached the market in 2012 confirming that medicinal chemistry remains a major source of innovation.. The largest part of gNME come from biotech and academic research centers; pharmaceutical companies being responsible for less than one third.. Orphan drugs (17) represent 38% of 2012 gNME,.reflecting a change in strategy relying now less on the commercialization of blockbusters and more on niche markets and rare diseases. The major therapeutic area in 2012 remains oncology with12 gNME followed by metabolic diseases with 9 gNME including innovative mechanisms of action such as the first gene therapy and dapagliflozine, a first in class for type 2 diabetes. By contrary, only two molecules have been approved for CNS diseases for the treatment of epilepsy and multiple sclerosis. 68% 32 % Biotech Pharma 57 % 43 % Biotech Pharma 68% 2011 2012 Evolution of the number of global New Chemical Entities (gNCEs)