World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients

Table 1 Main causes of death in developed and developing countries excluding malnutrition

People indevelopedcountries(2002)	Millions	People in Developing countries (2002)	Millions	Globally(2011)	Millions
Heart attack	3.08	LRTI	2.81	Heart attack	7.00
Stroke	1.78	HIV/AIDS	2.55	Stroke	6.20
LTB cancer	0.61	Heart attacks	2.53	LRTI	3.20
LRTI	0.45	Infections at birth	1.78	COPD	3.00
COPD	0.42	Diarrhoeal disease	1.53	Diarrhoeal disease	1.90
Colon, rectal cancer	0.35	Stroke	1.45	HIV/AIDS	1.60
Diabetes	0.24	Malaria	1.25	Diabetes	1.50
Self inflicted injuries	0.23	Tuberculosis	0.96	LTB Cancer	1.40
Hypertensive heart disease	0.23	COPD	0.76	Road injuries	1.30
All causes	13.43	All causes	27.12
Estimates 20061		Malnutrition	36.00	All causes	62.00

¹The total number of deaths globally in 2006 was estimated to be about 62 million, of which 32 million were related to hunger and malnutrition. COPD: Chronic obstructive pulmonary disease; LRTI: Lower respiratory tract infections; LTB cancer: Lung, tracheal and bronchial cancer. Adapted from ref[22-28].

Table 2 The largest health care companies in the world based on annual revenues

Rank	Company	Country	Total annual revenue(USD billions)
1	Johnson and Johnson	United States	61.90
2	Pfizer	United States	50.01
3	Roche	Switzerland	47.35
4	GlaxoSmithKline	United Kingdom	45.83
5	Novartis	Switzerland	44.27
6	Sanofi	France	41.99
7	Astra Zeneca	United Kingdom/Sweden	32.81
8	Abbott Laboratories	United States	30.76
9	Merck and Co.	United States	27.43
10	Bayer HealthCare	Germany	22.30
11	Eli Lilly	United States	21.84
12	Bristol-Myers Squibb	United States	18.81

The companies were ranked by revenue as of March 2010 according to their released 2009 annual reports.

Table 3 Examples of orphan-designated drug products with at least one marketing approval in the United States for a rare disease indication

Drug product name	Orphan indications
Alglucerase injection	Replacement therapy in Gaucher's disease
Alitretinoin	Acute promyelocytic leukemia
Alpha1-Proteinase Inhibitor	Cystic fibrosis
Ambrisentan	Idiopathic pulmonary fibrosis
4-Aminosalicylic acid	Crohn's disease
Amifostine	Chemoprotective agent in cancer
Anagrelide	Polycythemia vera
Anti-tac (human)	Prevention of acute graft-vs-host disease
Arsenic trioxide	Multiple myeloma, MDS, CML, CLL
Atovaquone	Toxoplasma gondii encephalitis
Azacitidine	Acute myeloid leukemia
Beractant	Newborn infants with pneumonia
Bosentan	Idiopathic pulmonary fibrosis
Busulfan	Primary brain malignancies
Calfactant	Acute respiratory distress syndrome
Canakinumab	Juvenile idiopathic arthritis
Capsaicin	Erythromelalgia
Cladribine	Non-Hodgkin's lymphoma, CLL, AML
Clofarabine	Acute myelogenous leukemia
Coagulation factor VIIa	Bleeding in Glanzmann thrombasthenia
Cysteamine hydrochloride	Huntington's disease
Cytarabine	Gliomas
Daunorubicin liposomal	Acute myeloid leukemia
Decitabine	Sickle cell anemia, CML, AML
Eculizumab	Dermatomyositis
Epoprostenol	Replacement of heparin in hemodialysis patients
Filgrastim	Myelodysplastic syndrome and AIDS
Fludarabine phosphate	Non-Hodgkins lymphoma
Heme arginate	Myelodysplastic syndromes
Idarubicin	AML in pediatrics, MDS and CML
Ifosfamide	Bone and soft tissue sarcomas
Iloprost solution for infusion	Heparin-associated thrombocytopenia
Indium111 pentetreotide	Neuroendocrine tumors
Interferon gamma-1b	Idiopathic pulmonary fibrosis
Lenalidomide	Mantle cell lymphoma and CLL
Levocarnitine	Pediatric cardiomyopathy
Mecasermin	Amyotrophic lateral sclerosis
Mecasermin rinfabate	Burns that require hospitalization
Melphalan	Cutaneous melanoma
Mesna	Inhibition of the urotoxic effects
Miglustat	Neurological manifestations
Mitomycin-C	Refractory glaucoma
Mycophenolate mofetil	Pemphigus vulgaris
Nilotinib	Gastrointestinal stromal tumors
Nitazoxanide	Intestinal amebiasis
Nitisinone	Alkaptonuria
Nitric oxide	Acute respiratory distress syndrome
Pentostatin	Cutaneous T-cell lymphoma and CLL
Porfimer sodium	Cholangiocarcinoma
Pralatrexate	Diffuse large B-cell lymphoma
Primaquine phosphate	Pneumocystis carinii pneumonia
Protein C concentrate	Replacement therapy in protein C deficiency
Procarbazine hydrochloride	Malignant glioma
Quinine sulfate	Non Plasmodium falciparum malaria
Rapamycin (mTOR) inhibitor	Tuberous sclerosis complex
Rifabutin	Mycobacterium avium disease
Riluzole	Huntington's disease
Sermorelin acetate	Induction of ovulation in women
Sodium phenylbutyrate	Sickling disorders
Sodium thiosulfate	Platinum-induced ototoxicity
Somatropin	Induction of ovulation in women with infertility
Succimer	Mercury toxicity and kidney stones
Synthetic human secretin	Diagnostic procedures in pancreatic carcinoma
Synthetic porcine secretin	Diagnostic procedures in pancreatic carcinoma
Temozolomide	Advanced metastatic melanoma.
Tetrabenazine	Moderate/severe tardive dyskinesia
Thalidomide	Graft vs host disease in BMT
Topotecan HCl liposomal	Gliomas
Tretinoin	Acute and chronic leukemia
Trimetrexate	Metastatic carcinomas
Vorinostat	Multiple myeloma and mesothelioma

ALL: Acute lymphoblastic leukaemia; AML: Acute myeloid leukaemia; CML: Chronic myeloid leukemia; CLL: Chronic lymphocytic leukaemia; MDS: Myelodysplastic syndrome; BMT: Bone marrow transplantation. Adapted from references[43-45].

Table 4 Examples of orphan-designated drug products with marketing approvals in the United States for both common and rare disease indication

Drug product name	Orphan indications
Adalimumab	Paediatric Crohn's disease
Aldesleukin	Primary immunodeficiency disease
Allopurinol	Ex vivo preservation of kidneys for transplants
Aminosidine	Tuberculosis and Mycobacterium avium
Azathioprine	Graft-vs-host disease
Aztreonam	Improvement of symptoms in bronchiectasis
Bevacizumab	Ovarian, stomach and pancreatic cancer
Bleomycin sulphate	Pancreatic cancer
Cetuximab	Pancreatic cancer
Cisplatin liposomal	Osteogenic sarcoma metastatic to the lung
Colchicine	Behcet's Syndrome
L-Cycloserine	Gaucher's disease
Cyclosporine	Prophylaxis and treatment of GVH disease
Cyclosporine A implant	Prevention of rejection in cornea transplant
Cyclosporine liposomal	Bronchiolitis obliterans
Doxorubicin	Hepatocellular carcinoma
Doxorubicin HCl liposomal	Soft tissue sarcomas
Doxorubicin nanoparticles	Hepatocellular carcinoma
Eflornithine HCl	Pneumocystis carinii pneumonia in AIDS
Epoetin alpha	Myelodysplastic syndrome
Erlotinib HCl	Malignant gliomas
Etidronate disodium	Degenerative metabolic bone disease
Everolimus	Gastroenteropancreatic tumors
Histrelin	Acute intermittent and other porphyries
Immuneglobulin	Juvenile rheumatoid arthritis
Infliximab	Chronic sarcoidosis
Interferon alfa-2a	Esophageal carcinoma
Peginterferon alfa-2a	Chronic myelogenous leukemia
Interferon alfa-2b	Ovarian carcinoma, brain tumors
Peginterferon alfa-2b	Chronic delta hepatitis
Metronidazole (topical)	Perioral dermatitis
Metronidazole	Pouchitis
N-acetylcysteine	Acute liver failure
Paclitaxel	Pancreatic cancer
Paclitaxel aqueous gel	Esophageal and brain cancer
Paclitaxel micellar	Ovarian cancer
Paclitaxel protein-bound	Stage IIB to IV melanoma
Sorafenib	Stage IIB through stage IV melanoma
Ribavirin	Haemorrhagic fever with renal syndrome
Rituximab	Immune thrombocytopenic purpura
Thiotepa	Haematopoietic stem cell transplantation
Tranexamic acid	Hereditary angioneurotic edema
Urofollitropin	Initiation and re-initiation of spermatogenesis
Ursodiol	Cystic fibrosis liver disease

GVH: Graft versus host. Adapted from ref[43-45].

Table 5 List of drugs approved for rare diseases in Europe

Rare diseasecategory	Drug product name (Indication)
Leukaemias, lymphomas and related diseases	Histamine dihydrochloride and Decitabine (AML)
	Ofatumumab (CLL)
	Nilotinib (CML)
	Mercaptopurine and Clofarabine (ALL)
	Cladribine (Hairy cell leukaemia)
	Ponatinib (Philadelphia chromosome positive ALL and CML)
	Dasatinib (CML and AML)
	Azacitidine (Myelodysplastic syndromes, CML, AML)
	Bosutinib (Philadelphia chromosome positive CML)
	Nelarabine (T-cell ALL and lymphoma)
	Brentuximab vedotin (Hodgkin lymphoma and anaplastic large cell lymphoma)
	Ruxolitinib (Primary and other myelofibrosis cases)
	Plerixafor (Lymphoma and multiple myeloma)
Carcinomas and related diseases	Sorafenib tosylate (Hepatocellular carcinoma, renal cell carcinoma)
	Mitotane (Adrenal cortical carcinoma)
	Mifamurtide (Osteosarcoma)
	Temsirolimus (Renal cell carcinoma and mantle cell lymphoma)
	Trabectedin (Soft tissue sarcoma, liposarcoma, ovarian cancer)
	5-Aminole-vulinic-acid hydrochloride (Malignant glioma)
	Thalidomide and Lenalidomide (Multiple myeloma)
Chelating drugs and haemoglo- binopathy related diseases	Deferoxamine, Deferiprone and Deferasirox (Iron overload in beta thalassaemia)
	Dexrazoxane (Anthracycline extravasation)
	Hydroxycarbamide (Sickle Cell Syndrome)
	Zinc acetate dehydrate (Wilson's disease)
	Eculizumab (Proxysmal nocturnal haemoglobinuria and haemolytic uraemia)
Pulmonary hypertension	Bosentan monohydrate (Pulmonary arterial and systemic sclerosis)
	Iloprost (Primary pulmonary hypertension)
	Ambrisentan and Sildanafil citrate (Pulmonary arterial hypertension)
Cystic fibrosis	Mannitol, Aztreonam and Ivacaftor (Cystic fibrosis)
	Tobramycin (Pseudomonas aeruginosa in Cystic Fibrosis)
Enzymes used as drugs	Velaglucerase alpha (Type 1 Gaucher disease)
	Alpha-glucosidase (Pompe disease)
	Galsulfase (Mucopolysaccharidosis VI)
	Idursulfase (Hunter syndrome)
	Proteolytic enzymes enriched in bromelain (Burns)
Drugs used in other rare conditions	Carglumic acid (Hyperammonaemia due to n-acetylglutamate synthase deficiency)
	Betaine anhydrous (Homocystinuria)
	Stiripentol (Severe myoclonic epilepsy in infancy)
	Pirfenidone (Idiopathic Pulmonary Fibrosis)
	Icatibant acetate (Hereditary angioedema)
	Amifampridine (Lambert-Eaton myasthenic syndrome)
	Alipogene tiparvovec (Familial lipoprotein lipase deficiency)
	Mecasermin (Growth failure in primary insulin-like growth factor 1 deficiency)
	Rufinamide (Lennox Gastaut syndrome)
	Sapropterin dihydrochloride (Phenylketonuria and tetrahydropterin deficiency)
	Romiplostim (Immune thrombocytopenic purpura)
	Nitisinone (Hereditary tyrosinemia type 1)
	Ibuprofen (Patent ductus arteriosus)
	Caffeine citrate (Primary apnea)
	Hydrocortisone (Adrenal insufficiency)
	Zicotide (Chronic pain)
	Teduglutide (Short Bowel Syndrome)
	Pasireotide (Cushing's disease)
	Thiotepa (Haematopoietic progenitor cell transplantation)
	Everolimus (Tuberous sclerosis complex)
	Tafamidis (Transthyretin amyloidosis)
	Anargelide hydrochloride (Essential thrombocythaemia)
	Miglustat (Type 1 Gaucher disease and Niemann-Pick type C disease)

ALL: Acute lymphoblastic leukaemia; AML: Acute myeloid leukaemia; CML: Chronic myeloid leukemia; CLL: Chronic lymphocytic leukaemia. Adapted from ref[46].

Table 6 Orphan diseases with the most orphan drug approvals

Disease	Drugdesignation	Drugsapproved
AIDS	57	8
Acute myeloid leukaemia	34	5
Ovarian cancer	34	4
Multiple myeloma	32	6
Glioma	29	4
Chronic myelogenous leukaemia	19	4
Acute lymphoblastic leukaemia	17	6
Pneumocystis carinii pneumonia	15	5
Respiratory distress syndrome, infant	14	6
Multiple sclerosis	14	5
Growth hormone deficiency	13	9
Idiopathic pulmonary hypertension	12	4
Kaposi's sarcoma	11	5
Malaria	11	4

Adapted from ref[48,49]. AIDS: Acquired immunodeficiency syndrome.

Table 7 Examples of neglected tropical and other diseases in developing countries

Disease categories	Diseases
Genetic diseases	Thalassaemias, sickle cell disease
Helminth infections	Ascariasis, hookworm, trichuriasis, schistosomiasis, lymphatic, filariasis, onchocerciasis, dracunculiasis
Protozoan infections	Human african trypanosomiasis chagas disease, leishmaniasis
Bacterial infections	Buruli ulcer, leprosy, trachoma
Environmental poisoning	Arsenate toxicity, bantou siderosis, mining industry, nuclear industry
Communicable and other diseases	HIV/AIDS, tuberculosis, malaria

HIV/AIDS: Human immunodeficiency virus infection/acquired immunodeficiency syndrome.