Orphan diseases and drugs

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					                                                                                                              Educational Forum

                                     Orphan diseases and drugs
                                                        G. K. Randhawa

                                        The World Health Organization defines orphan diseases, as all pathological conditions,
   Department of Pharmacology,          affecting 0.65-1 out of every 1000 inhabitants. They are usually not studied for their patho-
   Government Medical College,          physiology or for newer therapeutic options, as these are not economically viable. The
         Amritsar, Punjab. India        Orphan Drug Act was passed on January 28, 1983 by USA to stimulate the research, devel­
                                        opment, and approval of those products that treat orphan diseases. Till date, 11 drugs (4.87%)
            Received: 17.8.2005         for tropical infectious diseases have been designated with orphan drug status, and as many
             Revised: 24.2.2006         drugs for other infectious diseases. Several drugs with orphan status are used in the treat-
            Accepted: 20.3.2006
                                        ment of diseases that no longer meet orphan status criteria, such as AIDS and end-stage
          Correspondence to:            renal disease. Understanding of the human genome, nuclear cloning, rational drug design-
                  G. K. Randhawa        ing, and application of high throughput screening in drug discovery programs, might lead
  E-mail: g.kullar@rediffmail.com	      to new drug discoveries for orphan diseases. Hence, there is hope in future for patients
                                        neglected by for-profit drug discovery efforts.

                                        KEY WORDS: Drugs for neglected diseases initiative, neglected diseases, orphan drugs.

    The World Health Organization defines orphan/rare                galactosidase A), Lambert-Eaton myasthenic syndrome (an
diseases as, ‘all pathological conditions that affect 0.65-1 out     autoimmune disease of peripheral cholinergic system resulting
of every 1000 inhabitants’. The EU defines a rare disorder as        in muscle weakness due to impaired acetylcholine release),
one with a prevalence of 5: 10,000 Europeans; the USA accepts        and many more like Aarskog syndrome, Adams Nance
it as an ailment affecting fewer than 2,00,000 Americans (with       syndrome, Bagatelle Cassidy syndrome, Bamforth syndrome,
an incidence of less than 1/5,000 in the general population);        Ballard syndrome and Bahemuka Brown syndrome.
Japan has the limit at 50,000 Japanese patients and Australia            There are some familiar orphan/rare/neglected diseases,
at 2000 Australian patients.[1] There are approximately 6,000        like Alzheimer’s disease, ALS, Crohn’s disease, Hodgkin’s
orphan diseases, out of which 80% are genetic.[2] These diseases     disease, leukemia (many forms), multiple sclerosis,
are very much like children without parents, and as such,            Huntington’s disease, sickle cell disease, muscular dystrophy,
require special effort for the development of their treatment        myasthenia gravis, and spinal cord injury. All disorders due
options. But they are usually not studied for their                  to genetic defects in development (like spina bifida, Turner’s
pathophysiology or for newer therapeutic options,[3] as the          syndrome, Klinefelter’s syndrome, cleft lip and palate), and
inputs are not economically rewarding. Hence, treatment and          deficient enzymes (like cystic fibrosis, respiratory distress
diagnostic methods also have not yet been fully developed for        syndrome, Gaucher’s disease, hemophilia), are considered
them.                                                                orphan diseases. Tropical infectious diseases like malaria,
    Many orphan diseases are lesser known, like Juberg               leprosy, tuberculosis and leishmaniasis with lesser incidence
Marsidi syndrome (a genetic disorder of childhood that leads         in developed countries, may also be considered as orphan
to severe mental retardation, abnormal bone growth resulting         diseases there.
in the disfiguring of the head and body and loss of hearing),
                                                                     Concept of orphan drug
Hermansky-Pudlak syndrome (a group of genetically
heterogeneous disorders which share the clinical findings of             Medical melodrama in the early 1980’s in the US, set the
oculocutaneous albinism, platelet storage pool deficiency and        pace for the concept of orphan drug and its regulation. It
ceroid lipofuscinosis), Werdnig Hoffman disease (a fatal, fetal      depicted a young boy with Tourette syndrome, which generated
disease similar to amyotrophic lateral sclerosis (ALS), Omenn’s      the public opinion for unfortunate victims of these diseases.
syndrome (absence of mature B and T cells, children being            With this issue in the public eye, the Orphan Drug Bill was
born with late-stage ALS-like symptoms), Fabry’s disease (an         passed in 1981, but the US Congress stalled it.[4] A specific
X-linked lysosomal-storage disorder due to deficiency of             treatment of the orphan condition was not lucrative for the

                                                                              Indian J Pharmacol   | June 2006 |   Vol 38   |   Issue 3   |   171-76   171

pharmaceutical industry, as these medicines would be used                       Fast-track designation does not apply to a drug alone, but to
only by a small number of patients. There is a 13-fold greater                  the combination of a drug, and the specific indication being
chance of a medicine being brought to market for central                        studied. Drugs intended to treat a serious condition must be
nervous system disorder or cancer, than for a neglected                         therapeutic (treat a serious manifestation or symptom),
disease. [5] There was no incentive for the pharmaceutical                      diagnostic (improve detection or diagnosis), preventive
industry to spend time (around 10 years) and money (the cost                    (prevent serious consequences), or lack serious adverse
of bringing a new molecules approximately $350-500 million)                     effects. For fast-track designation, one of the two conditions
on unproductive ventures.[6] Moreover, research had to be                       must be met: (1) no therapy must exist for that specific
prioritized to make best use of available resources. This gave                  condition, (2) the new therapy must demonstrate an improved
rise to the concept of orphan drugs which lack sponsorship,                     effect, affect alternative outcomes other than the current
are expensive to investigate and develop, are used by few                       therapy, benefit patients unresponsive to current therapy, avoid
patients and bring inadequate rewards Therefore there is very                   serious toxicities associated with current therapy, or offer
little incentive for marketing these.[7]                                        improved compliance and convenience compared to current
                                                                                therapy. [15] Postmarketing surveillance for these drugs present
Need for orphan drug regulation
                                                                                concern because of small number of target patients. Potential
    Absence of specific treatment for orphan disease causes                     issues may include drugs approved for orphan status for
psychological distress to the patient and the family, and a                     diseases that no longer are considered rare (like AIDS), or
feeling of hopelessness sets in. Many diseases lacking specific                 drug approval based on surrogate endpoints that later do not
therapy are important targets for anecdotal therapy. Thus,                      demonstrate a traditional benefit. [Table 1]
unproven therapies and wrong beliefs prevail in quest of some                       FDA approvals for ODS are less, as compared with total
relief. USA was the first nation to propose a legal framework                   approval of new molecular entities. As can be seen from the
to encourage development and availability of orphan drugs.[8,9]                 above data, that percentage of orphan drugs for standard
The Orphan Drug Act (ODA) was passed on January 28, 1983,                       approvals is much less (0% in 2000 to 7.14% in 2004), as
which was an amendment of Federal Food, Drug and Cosmetic                       compared to priority approvals (22.22% in 2000 to 47.26% in
Act of 1938,[10] to stimulate the research, development, and                    2004). In 2005, no drug was approved for ODS. Except for
approval of products that treat orphan diseases. Drugs are                      2002, it is clear that the interest of pharmaceuticals for
granted orphan status for a specific indication, and still need                 development and subsequent approvals for ODS is lacking.
studies to demonstrate their safety and efficacy, unless these                  [Figure 1]
qualify for accelerated approval.                                                   Fast track approval has been granted to four drugs during
    The main incentives of achieving orphan drug status (ODS)                   these eight years for various conditions: Arsenic trioxide was
include:                                                                        approved on 25.09.2000 for treatment of acute promyelocytic
    � Tax incentives for clinical research,                                     leukemia, Imatinib mesylate on 10.05.2001 for chronic myeloid
    � Study design assistance from FDA ,                                        leukemia, nitisinone on 18.01.2002 for hereditary tyrosinemia
    � Exemption from application-filing fees,                                   type-I, and pegvisomant on 25.03.2003 for acromegaly. With
    � Grant for Phase I and II clinical trials, and                             the advent of ODA, considerable drugs (16.55%) are being
    �	 Seven years of marketing exclusivity after the approval                  developed for orphan diseases.
       of the drug or biological product [11]                                       Approval for ODS by FDA has been given to 269 drugs (as
    More than 10 million patients have been treated since the                   on 15.05.2005). Some of the agents approved for genetic/
inception of ODA, which has fueled research of orphan                           congenital diseases as replacement therapy, are recombinant
diseases. ODA exists in various countries like USA, Japan,                      enzyme imiglucerase and alglucerase (injection) in patients
Singapore, Australia, Canada, France, Sweden, and United                        with gaucher’s disease, antithrombin III (human) for congenital
Kingdom.[12] The basis of the initiative of other countries being               deficiency of AT-III, for prevention and treatment of thrombosis
the US ODA, with variations like marketing exclusivity rights                   and pulmonary emboli, alpha-1 proteinase inhibitor (human)
to the marketing company for 7 years in USA, 10 years in Japan,                 for alpha-1 proteinase inhibitor congenital deficiency state,
and 5 years in Australia. Other countries seeking to establish                  coagulation factor IX (human) for patients with hemophilia B
similar legislation include South Korea, New Zealand, and                       for the prevention and control of bleeding episodes, and during
India. A group of pharmacologists requested the Indian                          surgery to correct defective hemostasis, pegademase bovine
government to institute ODA at the conference held by the                       for ADA deficiency in patients with severe combined
Indian Drug Manufacturing Association in November 2001,[13]                     immunodeficiency, somatropin for growth hormone deficiency
but nothing concrete has materialized so far.                                   in adults after epiphyseal closure. Approved agents for
                                                                                treatment of some of the genetic diseases are felbamate,
Fast-track drug designation
                                                                                topiramate, and lamotrigine for Lennox-Gastaut syndrome,
    After the thalidomide tragedy, it was realized that more                    levocarnitine for carnitine deficiency, octreotide for acromegaly,
rigorous phase II and III clinical trials, were required prior to               riluzole for ALS, sacrosidase for sucrase-isomaltase deficiency,
approval for marketing of a drug. But in recent times, the                      tranexamic acid for coagulopathies receiving surgical
situation has changed. The AIDS crisis has prompted a swing                     intervention (e.g. dental extractions).
back from the expensive and rigorous pre-marketing review,                          Very few new medicines are being developed for orphan
to more expedited/fast track processes, with the intention of                   diseases. Current options for Wilson’s disease with neurologic
getting relief from fast spreading and fatal diseases. [14]                     manifestations, are anticopper drug-penicillamine (which often

172        Indian J Pharmacol   | June 2006 |   Vol 38   | Issue 3 |   171-76
                                                                                                                                                                          Orphan drugs

Table 1

An assessment of US-FDA approved orphan drugs (as assessed on 01.06.2005 from www.fda.gov/cder/rdmt)

 Year      Total drugs                          Approved orphan drugs                                                   Orphan                  PV/TP                            SV/TS
            approved                                                                                                      drug                  drugs                            drugs
                                                                                                                       designated                 %                                %

 1998          30          Lepirudin PV, sacrosidasePV, rifapentinePV, thalidomide PV, valrubicin PV,                          7                      6/16                        1/14
                           thyrotropin alfa PV, modafinil SV                                                                                         (37.5)                       (7.1)

 1999          35          Alitretinoin PV, temozolamide PV, exemestine SV, poractant SV, nitric oxide PV,                     6                  4/19                            2/16
                           bexarotene PV                                                                                                         (21.05)                         (12.5)

 2000          27          Gemtuzumab PV, arsenic trioxide PV, FTA                                                             2                   2/9                            0/18
                                                                                                                                                 (22.22)                           (0)

 2001          24          Imatinib mesylate PV, FTA, bosentan SV                                                              2                   1/7                            1/17
                                                                                                                                                 (14.28)                         (5.88)

 2002          17          Nitisinone PV, FTA, treprostinilsodium PV, sodium oxylate PV,                                       5                   4/7                            1/10
                           nitazoxanide PV, icodextrin SV                                                                                        (57.14)                          (10)

 2003          21          Pegvisomant PV, FTA, miglustatSV, prussian bluePV, bortezomib PV                                    4                   3/9                            1/12
                                                                                                                                                 (33.33)                         (8.33)

 2004          31          Pemetrexed disodium PV, cinacalcet hydrochloride PV,                                                9                  8/17                            1/14
                           apomorphine hydrochloride PV, azacitidine PV, L-glutamine SV,                                                         (47.06)                         (7.14)
                           pentetate calcium trisodium PV, pentetate zinc trisodiumPV,
                           clofarabine PV, Iloprost PV

 2005           3          none                                                                                                0                         0                         0

 PV: Priority review orphan drugs = Significant improvement compared to marketed products, in the treatment, diagnosis, or prevention of a disease. SV:
 Standard review orphan drugs = The drug appears to have therapeutic qualities similar to those of one or more already marketed drugs. PV/TP drugs: Priority
 review orphan drugs Vs Total priority review drugs for that year SV/TS drugs: Standard review orphan drugs Vs Total standard review drugs for that year. FTA:
 Fast track approval

makes the patient neurologically worse) and zinc (which is                        Figure 1. Assessment of orphan drug designation by US-FDA
slow acting) with many adverse effects. A newly developed
(2003) orphan drug ammonium tetrathiomolybdate acts
differently from previous anticopper medicines. It forms a
stable tripartite complex with copper and protein. An open­                                     80

label study of this (120 to 410 mg/day, for eight weeks with

maintenance therapy with zinc for 3 years) in 55 untreated,

newly diagnosed patients with neurological manifestations,                                      40
reported that it is highly effective in them.[16]
    About 2.7% of all the new medicines (1061) developed from                                   20
1975 to 1994, concerned tropical diseases. A few novel
medicines have been developed from veterinary medicine                                           0
(ivermectin) and military research, (halofantrine, mefloquine)                                        1998    1999      2000       2001       2002           2003         2004     2005
as orphan drugs. Analysis of pharmacopoeia resulted in the
development of artesunate, artemether, and arteether. Lesser                                                                 PV/TP drugs              SV/TP drugs
importance is being given to the development of newer
treatment options for tropical infectious diseases, which is of
concern to nations with endemicity of these diseases.
Combined effect of minimal development of pharmaceutical                          drugs for tropical infectious diseases, whose incidence is less
agents, development of chemoresistance to older medicines                         in developed countries, but common in tropical countries.
(chloroquine, sulfadoxine-pyrimethamine, aminopenicillins),                       Halofantrine and mefloquine have been approved as
affordability (second and subsequent generation molecules),                       antimalarials, whereas rifabutin, rifampin, rifapentine,
and the abandonment of major medicines (melarsoprol) pose                         isoniazid, pyrazinamide and aminosalicylic acid have been
hurdles in treatment of these diseases.[17] Our net search                        approved as antitubercular agents. Thalidomide and
revealed that, 11 drugs (4.87%) for tropical infectious diseases                  clofazimine have been approved as antileprosy, liposomal
have been designated with ODS, and as many medicines for                          amphotericin B for visceral leishmaniasis and eflornithine for
other infectious diseases. US FDA has approved various orphan                     sleeping sickness.

                                                                                                       Indian J Pharmacol   | June 2006 |   Vol 38   |   Issue 3   |   171-76             173

Table 2

US FDA approved orphan drugs for HIV and its complications

         Approved drug	                                                                  Treatment of approved condition

Alitretinoin                                         Topical treatment of cutaneous lesions in patients with AIDS-related Kaposi’s sarcoma

Atazanavir                                           HIV-1

Atovaquone                                           Prevention of Pneumocystis carinii pneumonia (PCP) in high-risk, HIV-infected patients defined by a
                                                     history of one or more episodes of PCP and/or a peripheral CD4+(T4 helper/ inducer) lymphocyte count
                                                     <200/mm 3

                                                     Treatment of AIDS associated PCP

Dronabinol	                                          For stimulation of appetite and prevention of weight loss in patients with a confirmed diagnosis of AIDS

Daunorubicin citrate liposome injection	 Patients with advanced HIV-associated Kaposi’s sarcoma

Emtricitabine	                                       HIV-1

Enfuvirtide	                                         Advanced HIV-1

Epoetin alfa	                                        Anemia associated with HIV infection or treatment

Ganciclovir sodium	                                  Cytomegalovirus retinitis in immune compromised patients with AIDS

Immune globulin intravenous, human	                 Infection prophylaxis in pediatric patients affected with HIV

Interferon alfa-2a (recombinant)	                    AIDS related Kaposi’s sarcoma

Interferon alfa-2b (recombinant)	                    AIDS-related Kaposi’s sarcoma

Megestrol acetate	                                   Patients with anorexia, cachexia, or significant weight loss (>10% of baseline body weight) and confirmed
                                                     diagnosis of AIDS

Paclitaxel	                                          AIDS-related Kaposi’s sarcoma

Pegademase bovine	                                   For enzyme replacement therapy for ADA deficiency in patients with severe combined immunodeficiency

Somatropin for injection	                            AIDS-associated catabolism/weight loss

Sulfadiazine	                                        For use in combination with pyrimethamine for the treatment of Toxoplasma gondii encephalitis in patients
                                                     with and without AIDS

Trimetrexate glucuronate	                            PCP in AIDS patients

Zalcitabine	                                         AIDS

Zidovudine	                                          AIDS related complex

    US FDA has approved albendazole as orphan drug for                                  high risk of developing this disease, respiratory syncytial virus
neurocysticercosis due to Taenia solium as: 1) chemotherapy                             immune globulin (Human) for prophylaxis of respiratory
of parenchymal, subarachnoidal and racemose (cysts in spinal                            infections in infants and young children, at high risk. The other
fluid) neurocysticercosis in symptomatic cases, and 2)                                  drugs with ODS are mafenide acetate solution for use as an
prophylaxis of epilepsy and other sequelae in asymptomatic                              adjunctive topical antimicrobial agent, when used under moist
neurocysticercosis and hydatid disease (cystic echinococcosis                           dressings over meshed autografts on excised burn wounds,
due to E. granulosus larvae or alveolar echinococcosis due to                           ofloxacin for bacterial corneal ulcers, sertaconazole for athletes
E. multilocularis larvae), amphotericin B lipid complex for                             foot and tobramycin inhalation for bronchopulmonary infection
invasive fungal infections, cromolyn sodium 4% ophthalmic                               of Pseudomonas aeruginosa in cystic fibrosis.
solution for vernal keratoconjunctivitis, daptomycin for
                                                                                        Hazards of orphan drugs
complicated skin infections, efalizumab for moderate to severe
psoriasis, ganciclovir intravitreal implant for cytomegalovirus                             Orphan drugs may be associated with greater hazard than
retinitis, gemifloxacin for acute exacerbation of bronchitis and                        other products, as ideal amount of clinical evidence is often
community acquired pneumonia. Others having been granted                                lacking. [18] For example, during clinical testing, 31% of orphan
ODS are liposomal amphotericin B for cryptococcal meningitis,                           drugs on the market had more pronounced adverse effects
lodoxamide tromethamine for vernal keratoconjunctivitis,                                than non-orphan medicinal products. Similarly after FDA
pentamidine isethionate for Pneumocystis carinii pneumonia,                             approval, 13% of orphan products provoked more side effects
prevention of Pneumocystis carinii pneumonia in patients at                             than anticipated.[19]

174            Indian J Pharmacol   | June 2006 |   Vol 38   | Issue 3 |   171-76
                                                                                                                                                   Orphan drugs

Orphan vaccines                                                                                                         .
                                                                     medical organizations like World Bank, WHO, UNDP One such
     In addition to orphan drugs, there are orphan vaccines for      initiative focusing on drugs for rare diseases is DNDi (Drugs
disease control, and the prevention of spread of contagious          for Neglected Diseases Initiative).[31]
diseases. Vaccines are expensive to develop for a small number       Future prospects
of rare infectious diseases, and for those important but
geographically limited diseases (such as arboviral or diarrheal),        It is anticipated that pharmacogenomics will result in the
involving a small number of people. Only eight vaccines              identification of more orphan diseases in future. Animal
registered with orphan status (seven for therapeutic indications     experimentation has shown that nuclear cloning, and gene and
e.g., cancer and sickle cell anemia and one to prevent an Asiatic    cell therapy, represent exciting new strategies for treating
infectious disease - Japanese encephalitis virus), have been         genetic diseases. Nuclear transfer of embryonic stem cells
developed.[20] Effective vaccine against common infectious           (derived from mouse cumulus or fibroblast cells) can be coaxed
diseases like malaria, tuberculosis, and dengue fever, being         into becoming somatic cells like myogenic cells, dopaminergic
still not available, tropical countries will have to find a way to   and serotonergic neurons, hematopoietic cells, or pancreatic
develop their own vaccine facilities, [21] from a centralized non­   islet like cells. Strategies like therapeutic cloning might prove
profit public enterprise.                                            to be the future of treatment of neurodegenerative diseases,
                                                                     and blood dyscrasias.[32] Adult stem cells could help to cure
Devices with ODS                                                     some rare diseases. Ethical considerations impede the
    Devices intended to benefit the patient by treating or           development of therapeutic cloning. [33]
diagnosing a disease or condition that affects or is manifested          As new technologies of drug designing are incorporated in
in fewer than 4,000 individuals in the US per year, paved the        drug discovery programs, application of these in orphan
way for Humanitarian Use Devices through The Safe Medical            diseases might lead to better results in a shorter span of time.
Devices Act of 1990.[22] Some of these are, thyrotropin alpha        International support for rare disease research is also providing
as an adjunct to diagnosis of thyroid cancer, synthetic porcine      stimulus and motivation, to overcome the financial barriers
secretin for use in diagnosis of gastrinoma associated               and encourage development of treatment, for rare diseases
Zollinger-Ellison syndrome, satumomab pendetide for                  throughout the world.[11] FDA also has come up to expedite
detection of ovarian carcinoma, pentastarch as an adjunct in         the availability of medications needed for its own public. Hence,
leukapheresis to improve the harvesting and to increase the          the future holds hope for patients who have been so far
yield of leukocytes by centrifugal measures and iobenguane           neglected due to profit oriented drug discovery efforts.
sulfate I 131 for use as a diagnostic adjunct in patients with       References
pheochromocytoma. Nuclear medicine scientists can take
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2,00,000 patients), it provides substantial market advantage         13.	 Ariely R. The Rise of Biopharmaceutical Orphan Drug Adoption. [Published:
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                                 24TH ANNUAL NATIONAL CONFERENCE
                               INDIAN SOCIETY FOR MEDICAL STATISTICS

      Date            : 1- 3 December 2006

      Venue : P S G Institute of Medical Sciences & Research, Coimbatore
      Theme : Medical Statistics and National Millennium Development Goals.
      Pre Conference Courses :                                             30th November 2006

      For further details, Please contact:
                                                                                   Dr. Anil C Mathew
                                                                                   Organizing Secretary,
                                                                                   Associate Professor of Biostatistics,
                                                                                   PSG Institute of Medical Sciences & Research,
                                                                                   Coimbatore-641 004, Tamil Nadu. India
                                                                                   Tel: 91-422-2570170 ext 5803 (O) or
                                                                                   91- 422- 5535177(R), cell: 9245287851 Fax: 91- 422-2594400
                                                                                   E-mail: dranilmathew@rediffmail.com; anilpsgmet@gmail.com
                                                                                   Website: www.psgimsr.in

                          Last date for Registration to Conference: 30th September 2006

176           Indian J Pharmacol   | June 2006 |   Vol 38   | Issue 3 |   171-76