Table 2.

First-in-class new molecular entities with orphan diseases designation approved by the US FDA between 1999 and 2012 that were informed by physiology.

NME	Year	Discovery strategy	Therapeutic area	Indication	MMOA	Ref.
Omacetaxine	2012	Phenotypic	Cancer	CML	Inhibition of translation of short-lived proteins	[33]
Bedaquiline	2012	Phenotypic	Anti-infective	Tuberculosis	Inhibition of ATP synthase	[34]
Vorinostat	2006	Phenotypic	Cancer	Cutaneous T-cell lymphoma	HDAC inhibitor	[35,36]
Nelarabine	2005	phenotypic	Cancer	T-cell acute lymphoblastic leukemia	Nucleoside prodrug incorporated into DNA leading to inhibition of DNA synthesis	[37–41]
Plerixafor	2008	Phenotypic	Cancer	Hematopoietic stem cell transplantation	CXCR4 inhibitor	[42]
Rufinamide	2008	Phenotypic	CNS	Seizures associated with Lennox–Gastaut syndrome	Prolongation of the inactive state of the sodium channel	[43,44]
Artemether/lumefantrine	2009	Phenotypic	Anti-infective	Malaria	Activation of reactive intermediates	[45,46]
Dalfampridine	2010	Phenotypic	CNS	Multiple sclerosis	Kv channel-blocker greatest affinity for slowly inactivating channels.	[47]
Cinacalcet	2004	Phenotype	Metabolic	Secondary hyperparathyroidism	Allosteric activator	[48]
Azacitidine	2004	Phenotype	Cancer	Myelodysplastic syndromes	Nucleoside	[49,50]
Nitazoxanide	2002	Phenotypic	Anti-infective	Antiprotazoan	Interference with pyruvate:ferredoxin oxidoreductase	[51,52]
Lomitapide	2012	Target	Metabolic	Homozygous familial hypercholesterolemia	Binds to microsomal triglyceride transfer protein	[53,54]
Vigabatrin	2009	Target	CNS	Seizures	Irreversble GABA inhibitor	[4]
Eltrombopag	2008	Target	Vascular	ITP	Thrombopoietin receptor agonist	[55]
Sorafenib	2005	Target	Cancer	Renal cell carcinoma	Multikinase inhibitor VEGFR/PDGFR/KIT	[56]
Bortezomib	2003	Target	Cancer	Multiple myelomas	Proteasome	[57] [58]
Bosentan	2001	Target	Cardiovascular	Pulmonary arterial hypertension	Endothenlin-1 receptor antagonists	[59]
Pasireotide	2012	Target	Metabolic	Cushing's disease	Somatostatin receptor agonists	[60]
Raxibacumab	2012	Biologic	Anti-infective	Anthrax	Human mAb against Bacillus anthracis toxin P	[61]
Teduglutide	2012	Biologic	GI	Short bowel syndrome orphan diseases	GLP-2 agonist resistant to dipeptidyl peptidase IV	[62]
Glucarpidase	2012	Biologic	Cancer	Toxic plasma methotrexate concentrations	Enzyme metabolizes methotrexate	[63]
Brentuximab vedotin	2011	Biologic	Cancer	Hodgkin's lymphoma and ALCL	Toxic warhead conjugated to ADC for selectivity	[4]
Yervoy	2011	Biologic	Cancer	Melanoma	mAb	[4]
Ofatumumab	2009	Biologic	Cancer	CLL	mAb	[4]
Romiplostim	2008	Biologic	Vascular	Idiopathic immune thrombocytopenic purpura	Fc-peptide fusion protein (peptibody) agonist at thrombopoietin receptor	[64]
Pegvisomant	2003	Biologic	Metabolic	Acromegaly	Growth hormone receptor	[65–67]
Alemtuzumab	2001	Biologic	Cancer	B-cell chronic lymphocytic leukemia	CD52 cytolytic antibody B-cells	[68]
Gemtuzumab	2000	Biologic	Cancer	Cancer	CD33 conjugate	[69]
Denileukin diftitox	1999	Biologic	Cancer	Cutaneous T-cell lymphoma	CD25-directed cytotoxin	[70]

ADC: Antibody drug conjugate; ALCL: Anaplastic large cell lymphoma; CLL: Chronic lymphocytic leukemia; CML: Chronic myelogenous leukemia; GI: Gastrointestinal; HDAC: Histone deacetylases; ITP: Chronic immune thrombocytopenia; mAb: Monoclonal antibody; NME: New molecular entity.