09/10/2008

Orphan drugs
• Definitions
• Legislation
• Prevalence and evolution
Orphan drugs • Slicing
Doctoral seminar (9-10-2008) • Cost
Thomas De Rijdt, PharmD
• Dispensing
• Raw materials
• Rare diseases: capita selecta
• Conclusions

Definition: “Orphan disease” Definition: “Orphan disease”

• The term orphan disease implies two separate but related • Prevalence less than …
concepts.
– USA : 1/200,000
– To describe diseases that are overlooked by doctors, and has been – Japan : 1/50,000
applied for example
applied, example, to Fabry
Fabry's
s disease,
disease alveolar echinococcosis,
echinococcosis variant
renal cancer, high myopia, and even some common conditions, such as – Australia : 1/2,000
endometrial cancer and tobacco addiction. – Europe : 5/10,000
– WHO : 6.5-10/10,000
– However, more specifically the term orphan disease is used to
designate diseases that affect only small numbers of individuals (so-
called health orphans). Aronson, Br J Clin Pharmacol. 2006 March; 61(3): 243–245

Aronson, Br J Clin Pharmacol. 2006 March; 61(3): 243–245

Definition: “Orphan disease”

Definition of “orphan drugs”
• A disease which has not been "adopted" by the pharmaceutical
industry because it provides little financial incentive for the
private sector to make and market new medications to treat or
prevent it.
www.medicinenet.com accessed 29-09-2008

• Lists of orphan diseases

– 5000 – 8000 known rare disorders
– Different organisations
• NORD : National organisation of rare diseases
EMEA/290072/2007
• NIH : National institutes of health
• Eurordis : European organisation of rare diseases
• Orphanet : Orphan drugs network
• The term "orphan drug" refers to a product that treats a rare
• … disease affecting fewer than 1 per 200,000 Americans
– Affecting 6-8 % of the population (EU : 25 million patients)
www.fda.gov , accessed 29-09-2008

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 09/10/2008

Where do they come from ? Legislation: orphan drug status

• Intentionally developed (eg Tasigna)
• Unintentionally developed (eg Thalidomide) • USA : Orphan drug act (ODA)
– Since January 1983
Target
g Market – Incentives to encourage companies
• Tax reductions
• Extended marketing exclusivity (+ 7 years)
Designer drugs – Success ?
Shelf drugs • ‘83 – ’04 : 250 drugs authorised
RIP • ‘73 – ’83 : 10 such drugs on market
Recreational/malafide use (e.g. PCP)
Orphan drugs Haffner, N Engl J Med. 2006 Feb 2;354(5):445-7
…

Procedure EMEA/COMP
Legislation: orphan drug status • EMEA protocol assistance
• Europe : EMEA – COMP • Start at day 1
– Committee on orphan medicinal products • Study by COMP
– Since 2000 (Verordening
(V d i (EG) 141/2000 dd 16-12-1999)
16 12 1999)
• Advice COMP at dayy 90
– Incentives to encourage companies • Advice tot EC
• Protocol assistance • Conclusion of EC
• Financial benefits (fee reduction) – Within 30 days
• Marketing exclusivity (10 years) • Publication
• European registration (all countries) – A new orphan drug is born
– Not yet authorised for marketing for desired
indication (other procedure)

Orphan Evolution 2001-2007 : ATC

ATC/Authoristion
ATC/authorisation
ATC/authoristaion
ATC/Autorisation
ATC/authoristaiondatedate
date
date 2001-2004
2001-2007
date 2001-2006
2001-2003
2001-2005

5%
7%
5%
3%5%
2%
5% 27%
30%
33%
34% 33%
38%
44% 42%
3%
2%
40% 5%
42% 4%
2%2% 3%
4%
7% 5%
5%
8% 5% 3%
5% 3% 5%
8% 8% 6%
6% 6%

Enzyme Antithrombotic Cardiac Antihypertensive Urologic Hypothalamic

Enzyme
Enzyme Antithrombotic
Antithrombotic Cardiac
Cardiac Antihypertensive
Antihypertensive Urologic Hypothalamic
Urological Antineoplastic
Hypothalamic Analgesic
Antineoplastic Other
Analgesic
AntineoplasticEnzyme Enzyme
Immunosuppressive
Antithrombotic Analgesic
Antithrombotic Antiepileptica
CardiacAntihypertensive
Antihypertensive Other Antineoplastic
Hypothalamic
Hypothalamic Antineoplastic

• It started with enzymetherapy

• Shift toward antineoplastic drugs

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 09/10/2008

Authorisation per administration route Prevalence …

Prevalence/10.000

4.0
3.5
49% 51% 3.0
2.5
2.0
1.5
1.0
0.5
Oraal 0.0
Parenteraal

•No specialised administration necessary in all cases.

•Treatment in ambulatory care is possible.

Rocket science at high cost ?

… slicing to orphan diseases
• Possible to slice a disease into types • Mostly academic research
– Subsidized by EC (EMEA)
• If prevalence small enough …
orphan
h disease.
di • Small patient populations
– Multinational, multicentric research
– Leukemia
• Started as 1 disease – Lower level of evidence (p<0.05 ??)
• AML, CML, ALL, CLL : common known – Case reports >> RCT
• Now 18 subtypes defined • Financial risk when not protected
– Different types recognized as orphan disease and treated
with orphan drugs (eg. chloretazine, oxaliplatin, …) USA
Y. Waknine, 2004

Rocket science at high cost ? Rocket science at high cost ?

• High-tech synthetisation • Simple molecule, same administration
– Enzymes : Aldurazyme, Myozyme, … – Wilzin (= zinc acetate capsules)
• Treatment of Wilson’s disease

• Older products, new name

– Thalidomide (Softenon) • Existing product, different name
– Hydroxycarbamide
• Hydrea versus Siklos
• Existing molecule, different route
– Sildenafil
– Pedea (= ibuprofen) • Viagra versus Revatio

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 09/10/2008

The right price ? The right price ?

• Very expensive therapies

-pharmacokinetic challenge to calculate cost-utility (QALY’s) ?
• Can raise ethical questions
-EMEA states that every citizen has the right to receive healthcare.
(Maastricht treaty, December 1991)

The right price ?

The right price ?
• From orphan to blockbuster
• Nitisinone : herbicide (low price)
– Remicade
= NTBC (€ 58 / 10 mg)
– Epogen
= Orfadin (= 5,8
5 8 M€/kg) 400 x The Orphan Drug Backlash
(Scientific American May 2003:71-77)

• Hydroxycarbamide
• Definition of ultra-orphan drugs
– =Hydrea (€ 0.1975 / 500 mg)
– Prevalence less than 0.18 / 10,000
– =Siklos (€ 600 / month) Orphan drugs and the NHS: should we value rarity
(McCabe, BMJ 2005;331:1016-1019)

The right price ? The right price ?

• Wilzin • Glivec € 2660 / box
– Zinc acetate capsules • Tasigna € 4226 / box
– Price € 1.25 / 50 mg
g • Myozyme € 556 / vial
– No UD packing
• Aldurazyme € 651 / vial
• Aspirin > 230 x price raw material
• Sprycel € 4528 / box
– Acetyl salicylic acid
• Savene € 10335 / vial
– Price € 0.08 / 100 mg
– UD packing Who will/can pay ?

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 09/10/2008

IPLEX(TM) is a complex
recombinant human insulin-like
growth factor-I (rhIGF-I) and its
predominant binding protein
IGFBP-3 (rhIGFBP-3).

Dispensing orphan drugs

• Expensive
– Reimbursed medication
• € 7,11 allowance per box
• While handling cost = 10 - 20 % of stock cost

• Risk management programs

– Thalidomide
– Revlimid (lenalidomide)
– …

Legislation
Raw materials
• Royal Decree 19-12-1997
• Orphan drugs regulated by EMEA
– Pharmacist has to use licensed materials
• If producing them is not lucrative • Magistral versus officinal preparations
– Not available as orphan
p drug
g • Certificate of analysis
– Not available as pharmaceutical grade – Update 2008 (to be published)
– Can be available as chemical grade • Better quality assurance by distributor
primary material • Magistral preparations only with licensed
– “Orphan raw materials” materials
– Request to adapt the RD
• A problem in tertiary care hospitals
• Use of orphan raw materials in hospitals

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 09/10/2008

Orphan Diseases Task Force (UZL)

Ethics versus politics
• Survey UZL
• Phosphomannose isomerase deficiency: – Over 100 orphan diseases reported
– A carbohydrate-deficient glycoprotein syndrome with
– 18 orphan drugs and 11 orphan raw materials
hepatic-intestinal presentation
– Can be treated by supplying D D-mannose
mannose to the patient – Total budget € 7,000,000 (2007)
– Not available as brand drug nor as raw material • Requested foundation of “Leuven
pharmaceutical grade
coordination center for rare diseases and
– Available as chemical grade substance (purity > 99.99 %)
their treatments”
– Not allowed by law – Purpose : administrative support
– Yet it makes the difference in quantity and quality of life • e.g. reimbursement by convention

Jaeken et al., A J Hum Genet 62 (1998), pp. 1535–1539 • Soon available: www.weesziektencentrale.be

Autosomal recessive Pompe disease

• Glycogen storage disease type II
• Autosomal recessive metabolic disorder
• Deficiency in the enzyme acid maltase
– Needed to break down glycogen
• Build-up of glycogen causes
– progressive muscle weakness (myopathy) and
affects various body tissues
(particularly in the heart, skeletal muscles, liver and nervous
system)

Pompe disease
• First described by Johann Pompe in 1932.
• Infantile, or early onset
– Noticed shortly after birth
– Symptoms: severe lack of muscle tone, weakness, enlarged liver and heart.
Mental function is not affected. Development normal for the first weeks or
months but slowly declines.
declines
– Most children die before age of 2 years by respiratory / cardiac complication.

• Juvenile and adult onset

– Symptoms: generalized muscle weakness and wasting of respiratory
muscles in the trunk, lower limbs, and diaphragm, respiratory distress,
headache at night. Intellect is not affected.
– A small number lives without major symptoms or limitations.

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 09/10/2008

Pompe disease
• Therapy
– Alfa-glucosidase
• Recombinant human enzyme
• Replaces the missing enzyme
• Breaks down glycogen.
– Prolongs ventilator-free
ventilator free survival and overall survival
– Studied by Genzyme
– Now commercial available as Myozyme

– Started in a study as alfa-glucosidase

• Frozen solution at -80 °C
• Cooled solution
• Lyophilized powder
• Commercial available

Pompe disease Fabry disease

• Preparation by pharmacist • Autosomal recessive metabolic disorder
– Preparation in LAF by hospital pharmacist • Deficiency in the enzyme alpha-galactosidase
– Started as study medication • Accumulation of a glycolipid in vessels and
• 2 hours stable after defrosting Æ patient had to come to hospital
• 8 hours stable after defrosting Æ medication transported by taxi tissue (globotriaosylceramide)
– Less expensive as hospital admission
• Symptomatical treatment
• Problem with aggregation during transport
– Company suggests no transport – Symptoms: skin lesions, cornea verticilla,
– Use of particle inline filter to protect patient
– Use of human albumine to buffer Æ problem solved
renal and cardiac complications
• 24 hours stable after preparation • Treatment by enzyme substitution
– Agalsidase alpha (Replagal)
• Therapy makes difference between live and dead – Agalsidase beta (Fabrazyme)
• Unpredictable prognosis • Infusion every 2-3 weeks

Pulmonary arterial hypertension Pulmonary arterial hypertension

• Symptoms
– Short breath, diziness, fainting, heart failure

• Arterial hypertension
y
– Vasoconstriction
– Right ventricle enlargment (pumping)
– Heart failure and long fibrosis
• Venous hypertension
– Left hearth failure Æ pooling blood in lungs
– Treatment : diuretic, betablocker, ace-inhibitor,
valvesurgery

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 09/10/2008

Pulmonary arterial hypertension Pulmonary arterial hypertension

• Treatment • Treatment
– Conventional: lifestyle changes, digoxin, diuretics, – Endothelian receptor antagonist
oral anticoagulants, and oxygen • Bosentan (Tracleer)
• Sitaxentan (Thelin)
– Prostaglandins:
• Epoprostenol (Flolan
(Flolan, synthetic prostacyclin)
– Continuous infusion in central venous catheter – Phosphodiesterase inhibitors
– Instability (t½ = 5’) : on ice during administration • Sildenafil (Viagra)
• Treprostinil (Remodulin) • Sildenafil (Revatio)
– IV
– Oral and inhalation in developping
– Surgery
• Iloprost (Ilomedine) : longer t½ • Lung transplant
– IV
– Inhalation : Ventavis (US)
– Varia
• Beraprost (oral – Japan and Korea)
• L-Arginine (Heartbar)

Parkinson
• Duodopa (Belgium)
– Need steady level of dopamine
– When regular treatment fails
• Severe parkinson,
parkinson on-off
on off fluctuations
• Swith oral Æ intestinal administration
– Variability plasma level : 38 Æ 17 %
– Levodopa and carbidopa in intestinal gel
– Administration by pump
•Very expensive therapy
– Stability 15 weeks in fridge; 16 h at 40°C
•Surviving until surgery – € 45,000 / year / patient
•Partially financed by BSF (limited resources / budget)

Wilson disease Wilson disease

• Autosomal recessive genetic disorder
• Copper accumulates in tissues
• Symptoms
– Liver disease (tiredness, hepatic encephalopathy, …)
– Neurological and psychiatric problems (cognitive
deterioration, Parkinson-like, migraine, depression,
psychosis, …)
– Keyser-Fleischer rings in eyes
– Calciumaccumulation in kidneys, cardiomyopathy,
hypoparathyroidism, …
• Treatment
– Low copper diet (mushrooms, nuts, chocolate, …)
– Copper chelation by penicillamin to reduce levels
– Zinc acetate to maintain low Cu-levels
• Activation of metallothionein, a protein in the gut, that
binds copper so it cannot be adsorbed and transported
to the liver.
– Liver transplant

8
 09/10/2008

Reflections
Conclusions
• Orphan drugs have a special status
• Orphan drugs – Prevalence, profit, availability, legislation, …
– Definition depends on continent
– Need depends on population • Similar ?
– Status versus needs (eg raw materials) – Compassionate use
– Mostly very expensive therapies – Medical need
– Mostly live saving for a small population – Conventions
– Pharmacist has an important role – Clinical trial
• Advising, preparing, dispensing, reimbursement
– Off label use (especially in pediatrics, …)
– EMEA is supporting • “Drug orphans” versus “Orphan drugs”
– Ethical discussions are possible

Orphan drugs in Europe Orphan drugs outside Europe

Geneesmiddel Vorm Actieve stof Firma Telefoon Fax Terugbetaling
Geneesmiddel Vorm Actieve stof Firma Telefoon Fax Terugbetaling? ADVATE fl inj 5 ml 500E Octocog alfa (recombinante stollingsfactor Baxter Hyland 02/650.18.86 02/650.18.55 Ja
ALDURAZYME fl 500E Laronidase Genzyme nv 02/714.17.10 02/714.17.09 Ja VIII)
ATRIANCE vial 250 mg/50ml Nelarabine Glaxo 02.656.26.01 02.656.24.95 Nee ADVATE fl inj 5 ml 1000E Octocog alfa (recombinante stollingsfactor Baxter Hyland 02/650.18.86 02/650.18.55 Ja
amp 6 mg Busulfan Pierre Fabre 02/556.49.90 02/522.78.98 Nee VIII)
BUSILVEX BERINERT amp 500E C1-esteraseremmer ZLB Behring 016/38.80.81 016/38.80.89 Nee
CARBAGLU tabl 200 mg Carglumic acid Orphan Europe 02/461.01.36 02/461.02.36 Ja
FERRIPROX tabl 500 mg Deferiprone OPG Medico 00 31 102 62 57 63 00 31 102 62 57 60 Ja
CYSTADANE gr poeder Betaïne Orphan Europe Benelux 02/461.01.36 02/461.02.36 Nee FLOLAN fl IV 500 mcg Epoprostenol Glaxo Smith Kline nv 02/656.26.01 02/656.24.95 Nee
DIACOMIT caps 500 mg Stiripentol Biocodex 00 33 141 24 30 00 00 33 141 24 30 04 Nee FLOLAN fl 1,5 mg + 2x50 ml solv Epoprostenol Glaxo Smith Kline nv 02/656.26.01 02/656.24.95 Nee
EVOLTRA Fl 20 mg Clofarabine Quintiles 00 31 23 567 0910 00 31 23 565 78 26 Nee
HELIXATE NEXGEN fl 250E Octocog alfa (recombinante stollingsfactor ZLB Behring 016/38.80.81 016/38.80.89 Ja
EXJADE tabl 125 & 250 & 500 Deferasirox Novartis Pharma 02/246.15.15 02/246.15/00 Ja
VIII)
mg
HELIXATE NEXGEN fl 500E Octocog alfa (recombinante stollingsfactor ZLB Behring 016/38.80.81 016/38.80.89 Ja
FABRAZYME fl inj 35 mg Agalsidase beta Genzyme nv 02/714.17.10 02/714.17.09 Ja
VIII)
GLIOLAN sir 30 mg/ml 5-Aminolevulinezuur Medac 03 897.19.00 03.897.19.19 Nee HELIXATE NEXGEN fl 1000E Octocog alfa (recombinante stollingsfactor ZLB Behring 016/38.80.81 016/38.80.89 ja
GLIVEC caps 100 & 400 mg Imatinib Novartis Pharma nv 02/246.15.15 02/246.15.00 Ja VIII)
tabl 100 mg Rufinamide Novartis Pharma nv 02/246.15.15 02/246.15.00 Nee ILOMEDINE amp 0,05 mg Iloprost-tromethamine Schering nv 02/712.85.00 02/725.43.00 Nee
INOVELON KOGENATE fl 250IU Octocog alfa (recombinant coagulation Bayer Pharma 02/535.65.39 02/539.00.88 Ja
LITAK amp 10 mg/5 ml Clabridine Lipomed 00 31 413 369 285 Nee factor VIII)
LYSODREN tabl 500 mg Mitotaan Laboratoire HRA Pharma 00 33 140 331 130 00 33 140 331 231 Nee KOGENATE fl 500IU Octocog alfa (recombinant coagulation Bayer Pharma 02/535.65.39 02/539.00.88 Ja
vial 50 mg Recombinant-human & glucosidase Genzyme NV 02/714 17 10
02/714.17.10 02/714 17 09
02/714.17.09 Ja factor VIII)
MYOZYME
KOGENATE fl 1000IU Octocog alfa (recombinant coagulation Bayer Pharma 02/535.65.39 02/539.00.88 Ja
NAGLAZYME amp 1 mg/ml Galsufase Biomarin 0477/89.60.40 051/63.53.47 Nee
factor VIII)
NEXAVAR tabl 200 mg Sorafenib tosylate Bayer 02/535.65.30 02/539.00.88 Ja NOVOSEVEN 4,8 mg (240KUI) Eptacog alfa (geactiveerd) Novo Nordisk 02/520.62.10 Ja
ONSENAL caps 200 mg Celecoxib Pfizer 02/722.03.97 02/721.42.65 Nee NOVOSEVEN 60 KUI (1,2 mg) Eptacog alfa (geactiveerd) Novo Nordisk 02/520.62.10 Ja
NOVOSEVEN 240 KUI (4,8 mg) Eptacog alfa (geactiveerd) Novo Nordisk 02/520.62.10 Ja
ORFADIN caps 10 mg Nitisinone Orphan Europe 02/461.01.36 02/461.02.36 Ja
PROLASTIN fl 40 ml 1000 mg Alpha1-Proteinase Inhibitor (Human) Bayer Pharma 02/535.65.39 02/539.00.88 Nee
PEDEA amp 10 mg/2 ml Ibuprofen Orphan Europe Benelux 02/461.01.36 02/461.02.36 Nee PROLEUKIN fl IV 1 mg 18 milj Recombinant humaan Interleukin-2 Red Swan pharma logistics 02/223.33.30 02/223.34.30 Ja
PHOTOBARR Fl 15 mg/ fl 75 mg Porfimer sodium Nee PULMOZYME inhal amp 2,5 mg/2,5 ml Dornasum alfa Roche nv 02/525.82.36 02/525.82.66 Ja
PRIALT Fl 100 mg/ml Ziconotide Eisai Pharma 00 44 1932 824123 00 44 1932 824323 Nee
REFACTO fl 500E Moroctocog alfa (recombinante Wyeth Pharmaceuticals nv 010/49.48.50 010/49.46.80 Ja
REPLAGAL vial 3,5 mg/3,5 ml Agalsidase alfa TKT – 5S AB 00 46 8 544 964 00 00 46 8 544 964 29 Ja coagulatiefactor VIII)
REVATIO tabl 20 mg Sildenafil Pfizer 02/722.03.97 02/721.42.65 Nee REFACTO fl 1000E Moroctocog alfa (recombinante Wyeth Pharmaceuticals nv 010/49.48.50 010/49.46.80 Ja
SAVENE Fl 500 mg Dexrazoxane Topotarget 33 1 41 27 73 45 45 39 17 98 98 Nee coagulatiefactor VIII)
REFLUDAN fl IV 50 mg Lepirudine Pharma Logistics 02/363.15.70 02/363.15.99 Ja
SOMAVERT amp 10mg/15 mg/ Pegvisomant Pfizer 02/722.03.97 02/721.42.65 Ja
RILUTEK tabl 50 mg Riluzole Sanofi Synthelabo nv 015/50.96.43 015/50.96.60 Ja
20mg
SOMATULINE autogel spuit inj 90 mg Lanreotide Ipsen nv 09/243.96.00 09/220.44.73 Ja
SPRYCEL tabl 20 & 50 & 70 mg Dasatinib Bristol-Myers-Squibb 02/352.76.11 02/352.75.66 Ja
SOMATULINE autogel spuit inj 60 mg Lanreotide Ipsen nv 09/243.96.00 09/220.44.73 Ja
SUTENT caps 12,5 & 50 mg Sunitinib Pfizer 02/722.03.97 02/721.42.65 Ja SOMATULINE autogel spuit inj 120 mg Lanreotide Ipsen nv 09/243.96.00 09/220.44.73 Ja
THELIN caps 100 mg Sitaxentan sodium Nee SOMATULINE P.R. fl IM 20 mg/ml Lanreotide Ipsen nv 09/243.96.00 09/220.44.73 Ja
tabl 62,5 & 125 mg Bosentan Pharma Logistics 02/363.15.70 02/363.15.99 Ja THALIDOMIDE tabl 50 mg Thalidomide 0800/496.84 0800/496.86 Ja
TRACLEER THYROGEN kit 2xvial 1.1 mg + 2x10 Thyrotropine alfa Genzyme nv 02/714.17.10 02/714.17.09 Ja
TRISENOX amp 10 mg/10 ml Arsenic trioxide Cell Therapeutics Ja ml opl
VENTAVIS Iloprost Nee THYROGEN pulv. vr. inj. 0,9 mg Thyrotropine alfa Genzyme nv 02/714.17.10 02/714.17.09 Ja
caps 25 & 50 mg Zinc acetate Orphan Europe Benelux 02/461.01.36 02/461.02.36 Nee TOBI amp opl vr neb 300 mg/5 Tobramycinum Solvay Pharma & Cie 02/422.27.11 02/422.27.99 Ja
WILZIN ml
XAGRID caps 0,5 mg Anagrelide Pharma Logistics 02/363.15.70 02/363.15.99 Ja
XENAZYNE tabl 25 mg Tetrabenazine John Bell-Croyden 00 44 20 79 35 55 55 00 44 20 79 35 96 05 Nee
XYREM 500 mg/ml Sodium oxybate UCB Pharma 02/559.92.26 Nee
ZEFFIX tabl 100 mg Lamivudine Glaxo Smith Kline 02/656.26.01 02/656.24.95 Ja
ZAVESCA tabl 100 mg Miglustaat Pharma Logistics 02/363.15.70 02/363.15.99 Ja

Orphan-like drugs in Europe (before 2000)

Geneesmiddel Vorm Actieve stof Firma Telefoon Fax Terugbetaling
AMMONAPS gran940mg/g; Natriumfenylbutyraat Orphan Europe Benelux 02/461.01.36 02/461.02.36 Nee
tabl500mg
BENEFIX fl 500E Nonacog alfa (recombinant Baxter Hyland 02/650.18.86 02/650.18.55 Ja
coagulation factor IX)
BENEFIX

BEROMUN

CEREZYME
fl 1000E

fl IV 1 mg

400E fl pulv. vr. inj.

Nonacog alfa (recombinant
coagulation factor IX)
Tasonermine

Imiglucerase
Baxter Hyland

Boehringer Ingelheim
nv
Genzyme nv
02/650.18.86

087/31.50.05

02/714.17.10
02/650.18.55

087/31.21.97

02/714.17.09
Ja

Ja

Ja
Thank you for
CYSTAGON caps 50 mg Mercaptamine Orphan Europe 02/461.01.36 02/461.02.36 Ja
CYSTAGON
ORLAAM
QUADRAMET
VITRAVENE
caps 150 mg
10 mg / ml

6,6 mg/ml: 0,25 ml

Mercaptamine
Levomethadyl HCl-acetaat
Samarium lexidronam pentanatrium
Fomivirsen natrium
Orphan Europe 02/461.01.36 02/461.02.36 Nee
Nee
Nee
Nee
your attention

Oliver Twist, story by Charles Dickens, 1838

9
Orphan drugs
D
Dooccttoorraall sseem
miinnaarr

0099--1100--22000088

Thomas De Rijdt

UZ Leuven – Ziekenhuisapotheek

Herestraat 49 – B3000 Leuven

Doctoral seminar of Thomas De Rijdt.

Title : Orphan drugs

Summary : Since medicine and diagnostics have been improved over the years it now is

possible to detect more rare diseases, commonly known as “orphan diseases”. Patients

with these diseases are treated with “orphan drugs” and as there is, by definition, no

commercial benefit in producing this medication it is very expensive to buy on the market

or even very scarse to find in a non-pharmaceutical quality of the raw material for use in

compounding. Nevertheless, in large tertiary care centres these drugs are requested nearly

daily.

As there’s specific legislation for production and registration of orphan drugs and as these

medication package is taking a large amount of money from the national healthcare budget

for a minority of the population, dispensing this products is not obvious.

In this presentation we’ll focus on the definition by EMEA, specific legislation concerning

production and registration, pharmaco-economics and some ethical questions.

Complementary an overview of the most common orphan drugs will be presented.

Thomas De Rijdt

Thomas De Rijdt – Doctoral seminar – Orphan drugs

Orphan drugs

Definition

Some diseases are overlooked by doctors (for example Fabry’s disease, alveolar

echinococcosis, variant renal cancer, high myopia and even common conditions as

endometrial cancer and tobacco addiction) and are therefore described as orphan diseases.

However, the therm “orphan disease” is more specially used to designate diseases that

affect only small number of individuals, the so called health orphans(1).

The definition of orphan diseases depends on the country. In the US orphan diseases have a

prevalence less than 1/200,000 Americans. In Japan prevalence has to be less than 1/50,000

while in Europe it has to be less than 5/10,000 and in Australia 1/2,000 citizens is the limit.

Most of these diseases have not been “adopted” by the pharmaceutical industy because they

provide little financial incentive for the private sector to make and market new medications

to treat or prevent them. Since 25 years different organizations like NORD (National

organization of rare diseases), NIH (National institute of health), Orphanet and Eurordis

(European organization of rare diseases) are listing up data. There are already 5,000 – 8,000

known rare disorders affecting 6 – 8 % of the population. For Europe we’re talking about

25 million patients(2).

All medicinal products intended for diagnosis, prevention or treatment of life-threatening or

chronically debilitating conditions affecting no more than 5 in 10,000 persons in the

European Union at the time of submission of the designation application at the European

Thomas De Rijdt – Doctoral seminar – Orphan drugs

Medicine Agency (EMEA) or when it is unlikely that expected sales of the product would

cover the investment in development without any incentive and if no such method already

exists and the products will be of significant benefit to the patients are designated as an

orphan medicinal product(3). Similar, the Food and Drug Administration (FDA) defined that

orphan drugs refer to products that treats rare diseases affecting fewer than 1 in 200,000

Americans(4).

As mentioned in the doctoral school program “From target tot market” in the development

of new drugs only few molecules make it to the market. Most of the unlucky molecules

become shelf drugs and will be forgotten in time. Sometimes they can live a second life as

recreational drug or orphan drug. Other orphan drugs are intentionally designed to treat a

rare disease.

Legislation

To encourage the pharmaceutical sector to market these products in January 1983 the US

government installed the Orphan Drug Act (ODA) which gives tax reductions and an

extend marketing exclusivity of 7 years to the companies. This act augmented the number

of authorized orphan drugs enormously(5). It took until the year 2000 before the European

Medicine Agency founded its committee on orphan medicinal product (COMP) and created

incentives to encourage companies to do research in the orphan drug segment. Therefore

they provide in protocol assistance, fee reductions, 10 year marketing exclusivity and central

European registration(6). Once the protocol is filed it takes maximum 120 days before the

European community refuses or publishes the status of orphan drug. From then the

Thomas De Rijdt – Doctoral seminar – Orphan drugs

company can request a marketing authorization for the desired indication and discuss a

vending price and eventually reimbursement can be required.

During time there’s been an evolution in therapeutic category of the authorized orphan

drugs. In 2001 – 2003 the majority of the molecules were enzymes and were used for the

treatment of metabolic diseases (42 %), followed by the category of antineoplastic drugs (34

%). Time shifted these numbers in the advantage of antineoplastic drugs while other smaller

groups made their entry. In 2001-2007 the situation was charactersized by antineoplastics

42 % and enzymes 27 %. In 2006 the American top 5 of drugs used in the treatment of rare

diseases showed similar rankings: cancer (38 %), metabolic diseases (37 %), infectious

diseases (23 %), neurologic disorders (18 %) and hematological disorders (16 %)(5).

Cost

As companies are encouraged to market drugs for the treatment of rare diseases it is

theoretically possible to slice a disease until the subtypes have a prevalence of less than 5 in

10,000 to benefit from the specified incentives. In the US chloretazine and oxaliplatin are

recognized as orphan drugs for treatment of leukemia (divided into 18 types)(7), in Europe

we find Glivec, Tasigna and Sprycel for treatment of chronic myeloid leukemia (CML).

The development of orphan drug isn’t rocket science but nevertheless it needs special

attention. Because of the small population research has to be organized international and

multicentric. Sometimes it is hard to proof a sufficient level of evidence and literature

shows often more case reports than fully randomized clinical trials. Some products are

Thomas De Rijdt – Doctoral seminar – Orphan drugs

hard to synthetize (eg enzymes) while others are nearly replica’s of older drugs (eg

thalidomide), aliases (eg Pedea, Siklos) or simple molecules (eg Wilzin).

Because of their orphan drug status these products are often given high vending prices (eg

Savene € 10335/vial, Tasigna € 4226/box, Myozyme € 556/vial, …) leading to enormous

therapy costs. A patient suffering from mucopolysccharidosis and treated with Aldurazyme

costs about € 300,000 / year to the community. In Belgium are 12 known patients. Such

amounts and numbers can be cited for all rare diseases. This huge impact on the budget for

such a little group of patients can lead to ethical discussions. In the Maastricht Treaty of

December 1991 EMEA stated that every citizen has the right to receive all proper needed

healthcare, including expensive treatment for rare diseases.

Nitisinone once was a low cost herbicide. Since it is used for treatment of tyrosinemea it

achieved a orphan drug status and is marketed as Orfadin at the price of € 58 per tablet.

This makes it 400 times more expensive than solid gold. An analog story can be told for

Siklos and Wilzin. Nevertheless this medication is sold a high prices manufacturers are not

always taking best care of packaging. This drugs are distributed in bottles in stead of high

quality unit dose packing.

There’s an important role for the pharmacist in dispensing orphan drugs. For the most

recent drugs the government demanded companies to set up a risk management program

(eg Revlimid, Thalidomide). Applying this program takes time and skills of the pharmacists

while they’re not paid for this work. Only € 7,11 is provided for covering the costs of

purchasing, keeping stock, handling, dispensing and follow-up.

Raw materials

Thomas De Rijdt – Doctoral seminar – Orphan drugs

Even with the European incentives for marketing orphan drugs not all needed molecules are

available as pharmaceutical while they’re needed to threat patients. Especially tertiary care

hospitals are dealing with this problem. Most of these molecules are available as raw

material in chemical or HPLC grade. The Royal Decree of 19-12-1997 stipulates that a

pharmacist can use non licensed materials for magistral compounding if they are analysed by

a certified laboratory. In the 2008 adaptation of the RD this will not be allowed anymore.

On request of the society of hospital pharmacist an addendum will be published to define

the conditions in which a pharmacist is permitted to use this raw materials. Until then a

pharmacist walks on the thin line between law and ethics.

Survey UZ Leuven

In 2007 UZ Leuven started an orphan diseases task force to survey the use of orphan drugs

in the hospital. Over 100 orphan diseases were reported, 18 orphan drugs and 11 orphan

raw materials are used with a budget of € 7,000,000 in the year 2007. UZ Leuven treats

over 2000 patients with orphan drugs. In 2008 the task force advised and requested the

foundation of the “Leuven coordination center for rare diseases and their treatments”

which purpose it is to support the administrative management related to rare diseases

(www.weesziektencentrale.be will be available soon).

Rare diseases: capital selecta

Pompe disease

In 1932 Johann Pompe first described an autosomal recessive metabolic disorder affecting

the enzyme acid maltase. The disease is also known as glycogen storage disease type II

Thomas De Rijdt – Doctoral seminar – Orphan drugs

because glycogen accumulates in the muscles because it cannot be breaked down due to the

enzyme deficiency. The infantile or early onset is noticed shortly after birth and most of the

children will die before the age of two of respiratory or cardiac complications.

Therapy exist in administering a replacing enzyme that can break down glycogen. In 2001

Genzyme coordinated a clinical trial with alpha-glucosidase. Only one patient was included

in Belgium.

Thanks to the therapy the patient could survive but is depended on a wheelchair and special

care. The hospital pharmacist had a big role in finetuning the method of preparation,

administration and was facilitator in studying extended stability of the solution. After 5-6

years the product Myozyme is available as orphan drug.

Fabry disease

A similar autosomal recessive metabolic disorder concerns the deficiency of the enzyme

alpha-galactosidase and leads to the accumulation of globotriaosylceramide, a glycolipid that

causes Fabry disease. For the treatment of this disorder two subtypes of the enzyme

agalsidase are available as Replagal and Fabrazyme.

Pulmonary arterial hypertension

For the treatment of pulmonary arterial disease five orphan drugs are authorized. This

disorder is characterized by an enlarged right ventricle due to difficult bloodflow in the

lungs caused by vasoconstriction and is leading to hearth failure and long fibrosis.

Conventional treatment exists of lifestyle changes, digoxin, diuretics, oral anticoagulants and

administration of oxygen but isn’t sufficient to let the patient survive.

A first breakthrough came with the availability of epoprostenol, a synthetic prostacyclin

(Flolan). With this therapy patients could survive until a donor for lung transplantation was

Thomas De Rijdt – Doctoral seminar – Orphan drugs

found. Besides a high cost to the community the therapy was hard for a patient to be

compliant. The prostaglandins have to be administered by continous infusion via a central

venous catheter. Due to its unstability (t½ = 5 minutes) the solution has to be kept on ice

during administration to slow down decomposition. Special pouches were developed to

carry the pump reservoirs in cooled conditions. Right now other prostaglandins like

treprostinil (Remodulin) and iloprost (Ilomedine) with other farmacokinetic parameters are

available and give patients more comfort and flexibility. In Asia en the USA oral

prostaglandins are available. Also endothelial receptor antagonists are influencing the

symptoms and can be used in therapy. In Belgium bosentan (Tracleer) and sitaxentan

(Thelin) are available for oral administration. In the group of phospdiesterase inhibitors

sildenafil (Viagra and Revatio) are available. Supplements of L-arginin are available as

supporting therapy. In the USA it is marketed as HeartBar, a “medicinal” candy-bar.

Parkinson disease

In some severe degrees of Parkinson disease a patient can have on-off fluctuations. This can

be explained by 38 % variability in plasma levels caused by the small half life of levodopa and

the erratically absorption in the stomach of severe Parkinson patients resulting in peaks and

throughs in the plasma levels. When levodopa and carbidopa are given in the jejunum this

variability drops back to 17 % while the patients on-off fluctuations disappears. The

intestinal gel is given by a CADD-pump through a nasal-jejunal probe (or a button). The

product is marketed as a ready to use solution with a stability of only 15 weeks in the

refridgerator and 16 hours at body temperature. The therapy has a cost of € 45,000 / year

/ patient.

Thomas De Rijdt – Doctoral seminar – Orphan drugs

Wilson disease

In 1912 Samuel Wilson first described an autosomal recessive genetic disorder which is

basically a accumulation of copper in the tissues of the body. The symptoms vary from liver

disease to neurological and psychiatric problems but one of the most typical is the presence

of a Keyser-Fleischer ring in the eyes. Besides copper also calcium is accumulated in the

kidneys. Patients often suffer from cardiomyopathy an hypoparathyroidism. The treatment

of Wilson disease is very simple and exists of a low copper diet combined with copper

chelation by penicillamin. But there’s also a natural way of binding the metal. Zinc acetate

activates methallothionein, a protein in the gut, that binds copper so it cannot be adsorbed

and transported to the liver. But in the end the patient will probably need a liver

transplant.

Conclusions

The definitions of orphan diseases and orphan drugs depend on the country and the need to

grant the status depends on the population. So a certain disease can be common in the

West while it is rare in the East. Once a product is recognized as an orphan drug the

manufacturer gets financial incentives to market the drug. In most cases this is related to a

high vending price resulting in very expensive therapies in which pharmacists play an

important role in advising, preparing, dispensing and managing financials (eg reimbursement).

In Europe EMEA is supporting and facilitating. The transparency of their assessment can be

seen in the online publication of the European Public Assesment Report (EPAR) in which

the full analysis of the request is written down.

In spite of the given incentives not al needed molecules are available as orphan drug. This

leads to problems in tertiary care hospitals where these drugs are needed on a nearly daily

basis to treat the rare patients. The Royal Decree of 1997 will forbid the use of non

Thomas De Rijdt – Doctoral seminar – Orphan drugs

licensed materials. In the 2008 adaptation the conditions in which a hospital pharmacist can

use these orphan raw materials wil be defined leading us out of the twilight zone.

Nevertheless ethical and macro farmaco-economical discussions in this domain will be of all

times.

Reflection

Orphan drugs is just a special status for medication that is needed to treat uncommon

diseases. But what is the difference with compassionate use, medical need, clinical trials,

conventions and off label use … aren’t they all just names to define a way in which people

can be helped when the commonly available medication fails to do the job ?

Thomas De Rijdt – Doctoral seminar – Orphan drugs

References:

1) Aronson, Br J Clin Pharmacol 2006 March; 61(3): 243-245.

2) www.medicinenet.com, accessed 29-09-2008.

3) EMEA guidelines : EMEA/290072/2007.

4) www.fda.gov, accessed 29-09-2008.

5) Haffner, N Engl J Med. 2006 Feb 2;354(5): 445-447.

6) EMEA guidelines : EG 141/2000 dd. 16-12-1999.

7) Y. Waknine, 2004, www.medscape.com, accessed 29-09-2008

Thomas De Rijdt – Doctoral seminar – Orphan drugs