PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

Transcription

1 PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES MANAGEMENT OF ORPHAN DISEASES AND CURRENT MARKET SCENARIO IN USE OF ORPHAN DRUGS: A REVIEW N. S. Vyawahare*, A. D. Kshirsagar, S. G. Narkhede, I. E. Ansari, A. M. Bhandare, V. G. Kagathara Department of Pharmacology, AISSMS College of Pharmacy, Kennedy Road, Near R.T.O. Pune , Maharashtra, India. ABSTRACT Orphan/rare disorders is the name given to the diseases of varied etiology with low prevalence rate and for the majority of which there is no treatment available while Orphan drugs' is the term given to those drugs, intended for the treatment of rare disorders. The number of patients affected is so small that it is not profitable to invest in research and development or to market them. Orphan diseases are often so rare that a physician may observe only one case a year or less. According to the ratios provided by the organizations of different countries amyotrophic lateral sclerosis, idiopathic thrombocytopenic purpura and other congenital coagulation disorders etc. could be considered to be rare disorders. Number of compounds that are undergoing discovery and development for treatment of orphan disease has increased significantly in recent years, but numbers of orphan drugs approved in last 25 years are still only a drop in bucket compared with many thousands of orphan diseases. Understanding of the human genome, nuclear cloning, rational drug designing and application of high throughput screening in drug discovery programs, might lead to new drug discoveries for orphan diseases. Hence, there is hope in future for patients neglected by for-profit drug discovery efforts. The present review covers the concept of orphan drugs, need for its regulation, incentives achieved after orphan status, global market of orphan drugs, and various strategies of pharma companies regarding orphan drugs along with introduction to some orphan diseases. Key words: Orphan drugs, orphan drugs Act, Gaucher disease. INTRODUCTION According to the World Health Organization orphan/rare diseases are 'all pathological conditions that affect out of every 1000 inhabitants. The European Union defines it as one with a prevalence of 5: 10,000 Europeans; the USA accepts it as an ailment affecting fewer than 2,00,000 Americans (with an incidence of less than IC VALUE 4.01 S - 217

2 1/5,000 in the general population); Japan has the limit at 50,000 Japanese patients and Australia at 2000 Australian patients [1]. There are approximately 6,000 orphan diseases, out of which 80% are genetic [2].These diseases are very much like children without parents and as such, require special effort for the development of their treatment options. But they are usually not studied for their pathophysiology or for newer therapeutic options as the inputs are not economically rewarding [3]. Hence, the treatment and diagnostic methods also have not yet been fully developed for them. Many orphan diseases are well known e.g. Alzheimer's disease, Crohn's disease, Hodgkin's disease, Leukemia (different forms), Multiple sclerosis, Sickle cell disease, Muscular dystrophy, Myasthenia gravis and Spinal cord injury. The disorders produced due to genetic defects in development like turner s syndrome, klinefelter s syndrome along with the deficient enzyme s disorders like cystic fibrosis, respiratory distress syndrome, hemophilia etc. are also comes under orphan diseases. Also, some tropical infectious diseases like malaria, tuberculosis, leprosy and leishmaniasis with their lesser incidents in developed countries may also be considered as orphan diseases. Many orphan diseases are lesser known e.g. Hermansky-Pudlak syndrome (a group of genetically heterogeneous disorders which share the clinical findings of oculocutaneous albinism, platelet storage pool deficiency and ceroid lipofuscinosis), Werdnig Hoffman disease, a fatal, fetal disease similar to amyotrophic lateral sclerosis (ALS), Omenn's syndrome (absence of mature B and T cells, children being born with late-stage ALS-like symptoms), Fabry's disease (an X- linked lysosomal-storage disorder due to deficiency of galactosidase A), Lambert-Eaton myasthenic syndrome (an autoimmune disease of peripheral cholinergic system resulting in muscle weakness due to impaired acetylcholine release). CONCEPT OF ORPHAN DRUG Medical melodrama in the early 1980's in the US set the pace for the concept of orphan drug and its regulation. It depicted a young boy with Tourette syndrome, which generated the public opinion for unfortunate victims of these diseases. With this issue in the public eye, the Orphan Drug Bill was passed in 1981 [4]. A specific treatment of the orphan condition was not lucrative for the pharmaceutical industry, as these medicines would be used only by a small number of patients. There is a 13-fold greater chance of a medicine being brought to market for central nervous system disorder or cancer, than for IC VALUE 4.01 S - 218

3 a neglected disease [5]. There was no incentive for the pharmaceutical industry to spend time (around 10 years) and money (the cost of bringing a new molecule approximately $ million) on unproductive ventures [6]. Moreover, research had to be prioritized to make best use of available resources. This ultimately gave rise to the concept of orphan drugs which lack sponsorship due to their expense in investigation and development, are used by few patients which bring inadequate rewards with availability of very little incentives for their marketing [7]. NEED FOR REGULATION OF ORPHAN DRUG: Absence of specific treatment for orphan disease causes psychological distress to the patient and the family with a feeling of hopelessness. USA was the first nation to propose a legal framework to encourage development and availability of orphan drugs [8,9]. The Orphan Drug Act (ODA) was passed on January 28, 1983, which was an amendment of Federal Food, Drug and Cosmetic Act of 1938 to stimulate the research, development and approval of products that treat orphan diseases [10]. Drugs are granted orphan status for a specific indication and still need studies to demonstrate their safety and efficacy, unless these qualify for accelerated approval. Following are the main incentives of achieving the status of orphan drug [12]. 1. Tax incentives for clinical research 2. Study design assistance from FDA 3. Exemption from application-filing fees 4. Grant for Phase I and II clinical trials and 5. Seven years of marketing exclusivity after the approval of the drug or biological product. Table 1: Classifications of orphan drugs Class Type Expected profits Available medication I Little/No Commercial benefit Poor Inadequate II Commercial benefit Good to excellent Inadequate III For rare disease that can currently be treated Variable Adequate IV Unprofitable for a common disease Poor Inadequate V Orphan for both rare and common disease Variable Variable IC VALUE 4.01 S - 219

4 Orphan drugs are classified on different basis. Table 1 represents a classification of five categories of orphan drugs based on their commercial potential and the availability of adequate treatment. Pharmaceutical industries consider both the stage of development as well as commercial and medical potential when describing or classifying orphan drugs. So, all the classification is relevant for the pharmaceutical industry. Drugs can shift from one category to other. A number of drugs have crossed from the type1 to type III categories over previous few years. These include Wilson's disease, which can now be treated with penicillamine, zinc and triethylenetetramine and rare bacterial diseases that can be treated with antimicrobials. Type I and III orphan drugs are usually the most difficult ones to find sponsors; therefore, even though the drugs are known to have activity but are yet not marketed. These drugs can become profitable type V drugs if these drugs are found to be effective in treating a common disease [13]. Table 2: Incentives for development of Orphan drugs in different countries INCENTIVES EU USA JAPAN Orphan Drug Regulation (CE) Orphan Drug Act Legal framework Regulation N 141/2000 (2000) (1983) (1993) Administrative authorities involved Market exclusivity Research grant EMEA / COMP 10 years normally (6 years if product is highly profitable) Available in some Member staye also central funding available from the EC Available in some FDA / OOPD MHLW/OPSR (Orphan Drug Division) 7 years 10 years Funded by office of orphan products development Funded by government Tax Reduction on development cost member state 50% 15% Waiver of fees Yes(variable) 100% Yes (variable) Protocol Assistance Yes Yes Yes Access to centralized procedure Access to continuous regulatory assistance Accelerated or fast track review Yes Yes -- Possible Possible Possible IC VALUE 4.01 S - 220

5 Sources: European Parliament STOA PUBLICATIONS- Orphan Drugs- PE, /Fin.St. Presentation of Prof Josep Torrent-Farnell (president of the COMP) at the 'Annual EuroMeeting 2001', Barcelona, 6-9 march 2001 Table 3: Orphan Medicinal Products for Human Use Product Active ingredient Company Summary indication Fabrazyme Agalsidase beta Genzyme Fabry disease Replagal Agalsidase beta shire Fabry disease Glivec CML Imatinib mesilate Novartis Chronic myeloid leukaemia Trisenox Arsenic trioxide Cephalon Acute promyelocyticleukaemia Tracleer Bosentanmonohydrate Aclelion Pulmonary arterial hypertension Zavesca Miglustat Aclelion Gaucher disease Somavert Pegvisomant Pfizer Acromegaly Aldurazyme Laronidase Pegvisomant Genzyme Ventavis Xagrid Iloprost Anagrelide hydrochloride Bayer Scheing Pharma Oral Onsenal Celecoxib Pfizer Mucopolysaccharidosis Pulmonary arterial hypertension Essential thrombocythaemia Familial adenomatous polyposis Litak Cladribine Lipomed GmbH Hairy cell leukaemia Photobarr Porfimer sodium Axcan Barrett's oesophagus Lysodren Mitotane Labortoire HRA Pharma Adrenal cortical carcinoma Pedea Ibuprofen Orphan Europe Patent ductus arteriosus Wilzin Zinc acetate dihydrate Oral Treatment of Wilson's disease Orfadin Nitisinone Oral Treatment of tyrosinaemia type I Prialt Ziconotide Intraspinal Treatment of chronic pain requiring intraspinal analgesia Carbaglu Carglumic acid Orphan Europe Busilvex Busulfan Pierre Fabre Limited Hyperammonaemia due to N-acetylglutamate synthase deficiency Haematopoietic progenitor cell transplantation IC VALUE 4.01 S - 221

6 Orphanet Report Series - List of the European marketing authorised Orphan Drugs. July 2008 Global Markets for Orphan Drugs: The global orphan drugs market reached $58.7 billion in 2006, growing by 8% from $54.5 billion in It is expected to grow at a compounded annual growth rate (CAGR) of 7% to reach $81.8 billion by Regionally, U.S. revenues in the market grew to $32.5 billion accounting for 55% of the market in The U.S. market is expected to grow at a CAGR of 8% to reach $47.8 billion by Biologic drugs account for over 60% of the orphan drug market with sales of $35.3 billion in 2006, up from $30.2 billion in The market size of biologic orphan drugs is projected to grow at a 9% CAGR to reach $53.4 billion by Table 4: Global orphan drugs demand by value, ($, Millions) Types of Drug CAGR Biologics % Non-Biologics % Total % As of mid-2003, 221 orphan drugs had been developed for the treatment of rare diseases affecting about 11 million patients. Some orphan products have sales in excess of $1 billion annually [14]. Big Pharmaceutical companies adopting orphan drug strategy: IC VALUE 4.01 S - 222

7 By anyone s standards, the Orphan Drug Act (ODA) of 1983 has proven remarkably successful in effecting the development of unique therapies for rare human diseases. It provides several economic incentives including tax credits on clinical trial expenses, grant funding by FDA, seven years of marketing exclusivity for a designated orphan drug, and a waiver of fees. The act makes it possible for biotechnology and pharmaceutical companies to reap a return on investments made on therapies for rare diseases, considered to be those that affect fewer than 200,000 people in the U.S. or, in the EU, five or fewer per 10,000 people.such diseases include hereditary enzyme deficiencies such as Gaucher and Fabry disease as well as multiple types of cancer. In the 10 years prior to 1983 when the ODA was passed, fewer than 10 pharmaceutical drugs or biologics for orphan diseases saw the light of day. As of April 2009, of the 1,994 orphan designations, 339 resulted in approval with market exclusivity. Market opportunity combined with the decreasing likelihood of success with the blockbuster drugdevelopment model is increasingly focusing big pharmaceutical companies on smallmarket, high-value therapies. U.S. orphan drug revenues reached $32.5 billion accounting for 55% of the market in Additionally, the U.S. market is expected to grow at a compound annual growth rate of 8%, reaching $ 47.8 billion by 2011 [14]. As gifts that keep on giving, orphan drugs can also be re-launched for nonorphan indications. For example, Rituxan was first approved in 1997 as a single agent for patients with relapsed or refractory, low-grade or follicular CD-20 positive, B-cell non-hodgkin lymphoma. Then in February 2006, it was sanctioned for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or other anthracyclinebased chemotherapy. Pharmaceuticals Latest Interest Pfizer s acquisition of Protalix s drug, taliglucerase alfa, for Gaucher disease bought it an instant Phase III stake in the hereditary enzyme disease arena, as did Shire s 2005 takeover of Transkaryotic Therapies (TKT), now Shire Human Genetic Therapies. These transactions put Pfizer and Shire in direct competition with Genzyme s Cerezyme when that company ran into manufacturing issues due to a plant closing. With the TKT IC VALUE 4.01 S - 223

8 purchase, Shire also obtained recombinant DNA technology and a protein-based drug pipeline, a significant departure from its pill-based heritage. The firm already markets Elaprase, originally developed at TKT, for Hunter syndrome; it received FDA approval in The drug costs between $300,000 and $400,000 annually [15]. Explanation of some orphan diseases: 1: GAUCHER DISEASE: Gaucher disease is probably the most common of the lysosomal storage disorders. Mutations of the gene encoding glucocerebrosidase result in accumulation of the substrate of this lysosomal enzyme, viz. glucocerebroside. As a result this glycolipid accumulates principally in the macrophages in type 1 disease, and in the neuronopathic forms of the disease (type 2 and type 3) in the central nervous system as well. Type 1 disease is by far the most common and is characterized by hepatosplenomegaly, thrombocytopenia, and often skeletal involvement. The management of patients with this autosomal recessive disease is possible by enzyme replacement therapy. Enzyme Replacement Therapy: The concepts behind enzyme replacement are not new. The idea that lysosomal storage diseases could be treated by exogenous administration of enzyme was first suggested by de Duve more than 40 years ago when he wrote:"any substance that is taken up intracellularly by an endocytic process is likely to end up within lysosomes. This obviously opens up many possibilities for interaction, including replacement therapy. Attempts to implement this strategy were carried out in the 1970s by Roscoe Brady's group at the NIH [16], the method of delivery that used, viz. encapsulating enzyme in red cell ghosts, was so cumbersome as to render this treatment approach impractical. The demonstration by Achord and Sly [17] in 1978 that macrophages have a mannose receptor that could be used to target exogenous enzyme to the cells was a major breakthrough.with the involvement of industry (Genzyme Inc.) it now became possible to make a targeted enzyme on a commercial scale and this enzyme was found to be very effective in treating type 1 Gaucher disease [18]. Substrate Reduction Therapy: IC VALUE 4.01 S - 224

9 The suggestion that inhibition of glucocerebroside formation may be helpful in treatment of this disease was first made verbally by Radin in the 1970's and in publication from almost 20 years ago by his group [19] and others [20]. The implementation of substrate reduction therapy was the indirect outcome of an unsuccessful trial of an enzyme inhibitor in the treatment of HIV infections. This inhibitor, now known as miglustat, is directed against the enzyme that transfers glucose to ceramide forming glucosylceramide (glucocerebroside). It had generally been thought that the use of such inhibitors, blocking the action of an enzyme so essential in glycolipid synthesis, would have prohibitively toxic side effects. But the use of this material in HIV infections made it clear that its toxicity was much lower than had been anticipated. The initial clinical trial showed that this inhibitor had distinct clinical activity in patients with Gaucher disease, reducing the size of both liver and spleen [21]. These investigations were confirmed in subsequent studies. The drug is somewhat less effective than enzyme replacement therapy, and has more side effects. These include gastrointestinal symptoms, neuropathies and tremor, all of which are believed to be reversible. 2. FABRY DISEASE: It is a fat storage disorder caused by a deficiency of an enzyme, alpha-galactosidase A (also called ceramidetrihexosidase), involved in the breakdown of fats. Since fat doesn't break down properly, part of it (globotriaosylceramide, also called Gb3 or GL-3) accumulates in the blood, blood vessels, and organs of the body and causes damage. The disease gene is mapped to Xq21-33 and Xq22, and more than 200 mutations have been identified. Fabry disease is inherited as an X-linked disorder, meaning that the defective gene is carried on the X (female) chromosome. This means that for a mother who carries the defective gene, each of her sons has a 50% chance of inheriting the disorder and each of her daughters has a 50% chance of being a carrier. Diagnosis of Fabry disease is suggested by the child's symptoms. A skin sample (biopsy) can be taken and examined under the microscope. Abnormal amounts of fat in the skin cells suggest Fabry disease. To treat this, anticonvulsant medications such as Dilantin (phenytoin) and Tegretol (carbamazepine) can be given to reduce the pain that Fabry disease causes. Other medications may be given to reduce the risk of heart attack IC VALUE 4.01 S - 225

10 or stroke.fabrazyme (algalsidase beta) is an orphan drug approved for treatment of Fabry disease that replaces the deficient alpha-galactosidase A enzyme. Studies have shown that this enzyme replacement therapy significantly reduces pain and helps keep the kidneys and heart healthy. Fabrazyme treatment is more effective when started early in the disease process 28. Onset is usually in childhood, with severe pain in the extremities, vesicular cutaneous lesions and corneal and lenticular opacities. The disease is rare with an estimated incidence of one in 40,000 males [22,23]. Autoimmune Disorders: 3: IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP): It is an autoimmune blood disorder in which the body in essence turns on itself and destroys its own cells. It is also called as immune thrombocytopenic purpura, a condition in which the body does not have enough platelets. Platelets are blood cells that help stop bleeding by sticking together to form clots that seal small cuts or breaks. The body usually makes antibodies to fight infection, but in ITP these antibodies attack and destroy the body s healthy platelets. What causes this is not known. ITP occurs in 50 to 150 people per million each year. About half of the people affected are children. There are two types of ITP a) Acute ITP is a temporary or short-term type of ITP which generally lasts for less than 6 months. It is the most common type of ITP and occurs mainly in children. b) Chronic ITP is long-lasting, usually causing symptoms for 6 months or longer. It mostly affects adults, but sometimes teenagers or children may develop it. Diagnosis of ITP: Diagnosis of ITP is made by review of one's medical history, physical examination and blood tests. During the history and physical examination, the doctor will look for signs of bleeding and for any other conditions that might cause low numbers of platelets in the blood. Blood tests include a complete blood count (CBC), which in ITP will show a low number of platelets. Treatment of ITP: IC VALUE 4.01 S - 226

11 Most children with the acute type of ITP recover completely from ITP in about 6 months with no treatment. Adults with mild ITP may not need treatment. Treatment of ITP focuses on increasing the number of platelets in the blood. For adults and children who need treatment, prednisone is usually taken for several weeks or months. Another medicine that may help increase the number of platelets is immunoglobulin. It is usually given intravenously. When patients don't respond to medicine, the spleen may be surgically removed from the body. In ITP, the spleen is thought to be an important site of antibody production and platelet destruction. However, removing the spleen may make a person more at risk for getting certain types of infections. Some people with ITP who have severe bleeding may receive a platelet transfusion. Donor platelets from a blood bank are injected into the person s blood to temporarily increase the number of platelets in the body. A medicine called Rituxan (rituximab) is being tried experimentally as a treatment for chronic ITP. It is also given intravenously. Several other medications are being tried as well. The Platelet Disorder Support Association maintains a list of ITP clinical trials which are in progress [23]. 4: TYROSINEMIA TYPE I METABOLIC DISORDER: Tyrosinemia type I is a metabolic disorder in which an enzyme critical for the breakdown of the amino acid tyrosine is missing. This allows abnormal amounts of tyrosine to accumulate in the body and act like a poison causing damage, especially in the liver. Tyrosinemia is an inherited disorder of chromosome 15 which affects males and females equally. In the United States it occurs in 1 of every 100,000 babies born. It is an autosomal recessive disorder, meaning that an infant must receive two copies of the defective gene for the disorder, one from each parent, in order to develop tyrosinemia type I. Symptoms: Different babies may have different symptoms of tyrosinemia type I. Some may show symptoms within the first few months of life (acute form); others may develop symptoms around 1 year of age (chronic form). Some symptoms acute form includes IC VALUE 4.01 S - 227

12 poor appetite and failure to grow normally,vomiting,diarrhea, bloody stools,a cabbagelike odor,jaundice (yellow skin and whiteness of eyes), swollen liver and irritability and lethargy (overwhelming tiredness). The symptoms of chronic form includes cirrhosis of the liver, tingling in parts of the body (polyneuropathy), kidney problems, episodes of intense abdominal pain, muscle weakness (Reference). Both forms of tyrosinemia type I may cause the liver to shut down (liver failure) and/or develop liver cancer. Diagnosis: The symptoms the infant has, especially the liver problems, usually suggest a diagnosis of tyrosinemia type I. Blood tests of liver function will abnormal. A urine test for succinylacetone is done; if it is present, it confirms the diagnosis. Treatment: There are three ways to treat the disorder. 1. Diet: The first thing to be done when a baby is diagnosed with tyrosinemia type I is to restrict the amount of tyrosine and another amino acid, phenylalanine, in the baby's food. There are special baby formulas that can meet this need. A dietary specialist helps families learn which foods are permitted and which are not. 2. Medication: Nitisinone (Orfadin, sometimes called NTBC) reduces the toxic effects of tyrosine in the body. The medication, when used along with the dietary restrictions, has been successful in reducing the symptoms of tyrosinemia type I and thus allowing children to be healthy and grow normally. 3. Liver transplant: In the past, a child with tyrosinemia type I would almost certainly need a liver transplant. Now, thanks to nitisinone, surgery is reserved for severe cases of liver damage or cancer. Transplantation carries many risks with it, including the rejection of the new liver by the body. Overall, early diagnosis and treatment provide the greatest benefits for the child with tyrosinemia type [24, 25]. 5: ZELLWEGER: It is an inherited peroxisomal metabolic disorder. Peroxisomes are found in almost all body cells and are responsible for many important cell processes. Zellweger IC VALUE 4.01 S - 228

13 syndrome causes a defect in the peroxisomes, which affects the body severely. Zellweger syndrome is estimated to occur in 1 of every 50,000 to 100,000 births. It affects both males and females and is present at birth. Symptoms: Zellweger syndrome affects many parts of the body, including head and face where it produces enlarged head, high forehead, large anterior fontanelle ("soft spot"), malformed ear lobes and flat-looking face (Reference). In brain and nervous system, it produces abnormal brain development which leads to seizures, hearing and vision impairment, profound mental retardation and developmental delay, diminished or absent reflexes, enlarged liver with impaired function, jaundice, renal cysts, hydronephrosis, very low muscle tone, bone defects in the hands, legs, and feet. Diagnosis: The distinctive shape of the head and face of the infant born with Zellweger syndrome provides a clue to the diagnosis. Zellweger syndrome causes the build-up of very-long-chain fatty acids (VLCFA), so a test for VLCFA can help confirm the diagnosis. Treatment: Despite the progress research has made in understanding Zellweger syndrome, no cure yet exists, and infants born with the disorder usually die within the first year of life (Reference). Medical care focuses on treating the symptoms present, such as liver dysfunction and seizures [26]. 6: ZOLLINGER-ELLISON SYNDROME (ZES): It is a rare disorder that causes one or more tumors to form in the pancreas or the upper part of the small intestine called the duodenum. It can also cause ulcers to develop in the stomach and the duodenum. The tumors are called gastrinomas, and they secrete a large amount of the hormone gastrin. This then causes an excessive production of stomach acid, which can lead to peptic ulcers (Reference). Zollinger-Ellison syndrome is rare, and though it may occur at any age, people between the ages of 30 and 60 are more likely to develop it. Also, of all the people who suffer with a peptic ulcer, only a tiny IC VALUE 4.01 S - 229

14 percentage of those people will have Zollinger-Ellison. The tumors are cancerous in 50 percent of the cases. They secrete a hormone called gastrin that causes the stomach to produce too much acid, which in turn causes stomach and duodenal ulcers (peptic ulcers). The ulcers caused by ZES are less responsive to treatment than ordinary peptic ulcers. What causes people with ZES to develop tumors is unknown, but approximately 25 percent of ZES cases are associated with a genetic disorder called multiple endocrine neoplasia. Symptoms: Various symptoms include snawing, burning pain in the abdomen, sensation of pressure, bloating, or fullness etc. The pain usually develops 30 to 90 minutes after a meal, and is often relieved by antacids. Pain or burning sensation in the abdomen that travels up toward the throat which is caused by heartburn, or gastroesophageal reflux, and occurs when stomach contents back up into the esophagus. Vomiting, diarrhea, blach stool etc. are some other symptoms. Treatments: The treatment of Zollinger-Ellison syndrome focuses on two areas: treating the tumors and treating the ulcers. Surgery in the treatment for tumors in Zollinger-Ellison Syndrome is often performed if there is only one tumor. If tumors are in the liver, a surgeon will remove as much of a liver tumor as possible (debulking). When surgery on tumors isn't possible, other treatments are used. Other methods includes attempts to destroy the tumor by cutting off the blood supply (embolization) can also be used, to destroy cancer cells by using an electric current (radio-frequency ablation), injecting drugs into the tumor to relieve cancer symptoms, use of chemotherapy to try to slow tumor growth. Treatment for ulcers in Zollinger-Ellison Syndrome includes the use of proton pump inhibitors and acid blockers [27]. 9: WILSON S DISEASE: It is a rare autosomal recessive genetic disease resulting from copper toxicity, primarily in brain and liver. The disease is caused by mutations in the ATP7B gene, IC VALUE 4.01 S - 230

15 which functions in a biliary copper excretory pathway [28, 29]. Failure of biliary excretion of excess copper leads to a slow accumulation of copper to the point of toxicity. In Western countries patients typically present with liver or neurologic disease in the second and third decades of life, although overall age of presentation can be quite broad (age 5 60 years). Patients presenting with liver disease may present with a hepatitis or recurrent hepatitis picture, cirrhosis, or liver failure. Patients presenting neurologically have symptoms of a movement disorder, often with dysarthria, dysphagia, incoordination, tremor, and dystonia occurring in any combination. Often patients present with behavioral abnormalities before developing neurologic symptoms [29].These include depression, loss of emotional control, inability to focus on tasks, loss of inhibitions, and occasionally, bizarre behavior (Reference). Screening tests include 24 h urine copper, Kayser-Fleischer ring examination by slit lamp, and serum copper and ceruloplasmin assays. The definitive diagnostic test is percutaneous liver biopsy with quantitative assay of copper. Mutation analysis is generally not useful because of the large number of causative mutations. Treatments: a) Anticopper drugs 1) Penicillamine: Penicillamine has been available longer than the other anticopper drugs, and is therefore best known to physicians. However, it has serious short-comings of toxicity and neurologic worsening and is being replaced by other equally effective, and less toxic, drugs. Penicillamine is a reductive chelator, and acts to mobilize copper from hepatic and other stores, and cause its excretion in the urine. The usual dose is 1.0 g/day, given as 500 mg twice daily or 250 mg four times daily. Each dose should be given at least half an hour before meals or at least 2 h after meals. It is not uncommon in a newly treated patient to see urinary excretion of 5 10 mg of copper/day (normal is mg/day, in untreated Wilson s it typically ranges from 100 to 1000 mg/day). As treatment proceeds the freely available copper pool is lessened, and the urine copper decreases, often to mg/day. Pyridoxine in a dose of 25 mg/day must be taken by patients IC VALUE 4.01 S - 231

16 on penicillamine therapy to avoid pyridoxine deficiency. Penicillamine is fully effective in Wilson s disease as long as the patient complies adequately. 2) Trientine: Trientine was introduced in 1982 as an alternative treatment for Wilson s disease patients intolerant of penicillamine and has been approved by the US FDA copper, and has nothing to do with the direct therapeutic action of the drug. 3) Zinc: Zinc was approved in 1997 by the US FDA for the maintenance therapy of Wilson s disease. Zinc acts by a novel mechanism. It induces intestinal cell metallothionein and inhibits the absorption of copper. The dose is 150 mg/day, in three divided doses, each dose separated from food and beverages other than water by at least 1 h. Zinc is fully effective in Wilson s disease as long as the patient complies with therapy [30]. 10) HERRMANSKY-PUDLAK SYNDROME (HPS): It is rare, autosomal recessive disorder characterized by the classic triad of oculocutaneous albinism, platelet dysfunction, and ceroid deposition within cells of the mononuclear phagocytic system. An associated complication with a variable expression is pulmonary fibrosis with progressive restrictive lung disease. Emphasizing the radiological and pathological manifestations in the lung, we report two siblings with HPS who developed pulmonary fibrosis [31]. 11) OMENN'S SYNDROME: It is also a rare inherited immunodeficiency disorder of infancy, characterized by a diffuse, erythematous, scaly rash; recurrent infection; protracted diarrhea; lymphadenopathy; hepatosplenomegaly; peripheral blood lymphocytosis and eosinophilia; and lymphocytic infiltration in the skin, gut, liver, and spleen. Since the syndrome was first described in 1965 by Omenn, other cases have been reported, broadening the spectrum of its clinical manifestations and immunologic abnormalities [32]. CONCLUSION IC VALUE 4.01 S - 232

17 The management of rare disease is a challenging problem for all countries. Legislation has defined rare or orphan disease by arbitrary disease prevalence, which grants incentives to Orphan Medicinal Product producers. There are over 5000 rare diseases which need more attention due to lack of proper diagnosis and treatment. Treatment and prevention for rare diseases is considered as 'no man's land. The EU parliament should provide more benefits like tax incentive, special status and reimbursement for these orphan drugs. This encouragement can bring in a revolution amongst the pharmaceutical and biotechnology companies for developing and marketing orphan drugs. EURODIS (European Organisation for Rare Diseases) and other organisations are creating awareness on rare diseases and are also influencing governments in bringing legislation acts for better quality of life for these special people. EURORDIS and National Alliances have announced "rare day" on February 29th and dedicated this day to special people who are affected by rare diseases. Henceforth 29th February will be called "The Rare Disease Day. IC VALUE 4.01 S - 233

18 REFERENCES 1. Lavandeira A. Orphan drugs: Legal aspects, current situation. Haemophilia 2002; 8: Campos-Castello J. Orphan drugs and orphan diseases. Rev Neurol 2001;33: Loizzo A, Tebano MT. Orphan diseases. Recenti Prog Med 1993;84: Henkel J. How TV Launched the Orphan Drug Law. FDA Consumer Magazine. Available from: 5. Trouiller P, Olliaro P, Els Torreele orbinski J, Laing R, Ford N. Drug development for neglected diseases: A deficient market and a public-health policy failure. Lancet 2002;359: Swoboda ML. The ethics of pharma-economics: An examination of the limit of corporate responsibility in the pharmaceutical industry Martinez-Pardo M. Orphan drugs and metabolic disorders. Rev Neurol ; 33: Haffner M. Orphan products: Origins, progress and prospects. Annu Rev Pharmacol Toxicol 1991;31: Haffner M, Kelsey J. Evaluation of orphan products by the US. Food and Drug Administration. Int J Tech Assess Health Care 1992;8: Katzung BG. Basic and clinical pharmacology. 9th ed. New York: McGraw Hill Haffner ME. Developing treatments for inborn errors: Incentives available to the clinician. Mol Genet Metab 2004;81: IC VALUE 4.01 S - 234

19 12. Thamer M, Brennan N, Semansky R. A cross-national comparison of orphan drug policies: implications for the US Orphan Drug Act. J Health Pol Policy Law 1998;23: Spilke B.Ophan drugs in comprensive medicinal chemistry,kennewell PD,editor,Vol 1. Oxford:Pargamon Press; P Global Markets for Orphan Drugs Report Code:PHM038B,Published: September 2007,Analyst: Syamala Ariyachira, [accessed 2010 Jan 10]. Available from: Genetic engineering news, dated 14/12/09 [accessed 2010 Jan 10]. Available from: Brady RO, Pentchev PG, Gal AE, Hibbert SR, Dekaban AS. Replacement therapy for inherited enzyme deficiency. Use of purified glucocerebrosidase in Gaucher's disease. N Engl J Med 1974;291: Achord DT, Brot FE, Bell CE, Sly WS. Human beta-glucuronidase:in vivo clearance and in vitro uptake by a glycoprotein recognition system on reticuloendothelial cells. Cell 1978;15: Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, Doppelt SH, Hill SC, et al. Replacement therapy for inherited enzyme deficiency-macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991;324: Inokuchi J, Radin NS. Preparation of the active isomer of 1-phenyl-2- decanoylamino-3- morpholino-1-propanol, inhibitor of murine glucocerebroside synthetase. J Lipid Res 1987;28: IC VALUE 4.01 S - 235

20 20. Lev M, Sundaram KS. Gaucher's disease. N Engl J Med 1987;317: Cox T, Lachmann R, Hollak C, Aerts J, van Weely S, Hrebicek M, et al. Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 2000;355: Desnik RJ, Ioannou YA, Eng MC. a-galactose A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Shy WS, Valle D, editors. The metabolic and molecular bases of Inherited diseases: 8th ed. McGraw Hill Book; chapter 150, p From Mary Kugler, R.N., former About.com GuideUpdated: May 05, Tyrosinemia Type I and II [accessed 2010 Jan 12 ]available from dicine. com/ped/topic2339.htm 25. The Pediatrician's Guide to Tyrosinemia Type I. National Organization for Rare Disorders, Grayer, J. (2005). Recognition of Zellweger syndrome in infancy. Adv Neonatal Care, 5(1), Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: A Pathophysiologic Approach, Sixth Edition; Brewer GJ. Wilson s disease: a clinician s guide to recognition.boston: Kluwer Academic; Brewer GJ, Fink JK, Hedera P. Diagnosis and treatment of Wilson s disease. Semin Neurol 1999;19: and use of prognostic index. Gut 1986;27: IC VALUE 4.01 S - 236

21 30. Walshe JM. Penicillamine, a new oral therapy for Wilson s disease. Am J Med 1956;21: Mark S. Parker, The Hermansky-Pudlak Syndrome, Annals of Diagnostic Pathology, Vol 1, No 2 (December), 1997: pp Anna Villa, MD, Omenn syndrome: Inflammation in leaky severe combinedimmunodeficiency, J allergy clin immunol, volume 122, number 6:p.1083 For Correspondence: Mr. Neeraj S Vyawahare Department of Pharmacology, AISSMS College of Pharmacy, Kennedy Road, Near R.T.O., Pune , India , neerajsv@rediffmail.com IC VALUE 4.01 S - 237