Orphan Drugs Doctoral Seminar

09/10/2008

Orphan drugs • • • • • • • • •

Orphan drugs Doctoral seminar (9-10-2008) Thomas De Rijdt, PharmD

Definitions Legislation Prevalence and evolution Slicing Cost Dispensing Raw materials Rare diseases: capita selecta Conclusions

Definition: “Orphan disease”

Definition: “Orphan disease”

• The term orphan disease implies two separate but related concepts.

• Prevalence less than …

– To describe diseases that are overlooked by doctors, and has been 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 endometrial cancer and tobacco addiction. – However, more specifically the term orphan disease is used to designate diseases that affect only small numbers of individuals (socalled health orphans).

– – – – –

USA Japan Australia Europe WHO

: 1/200,000 : 1/50,000 : 1/2,000 : 5/10,000 : 6.5-10/10,000 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 NIH : National institutes of health Eurordis : European organisation of rare diseases Orphanet : Orphan drugs network …

EMEA/290072/2007

• 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)

Target g

• USA : Orphan drug act (ODA) Market

– Since January 1983 – Incentives to encourage companies • Tax reductions • Extended marketing exclusivity (+ 7 years)

– Success ?

Designer drugs Shelf drugs RIP Recreational/malafide use (e.g. PCP) Orphan drugs …

• ‘83 – ’04 : 250 drugs authorised • ‘73 – ’83 : 10 such drugs on market Haffner, N Engl J Med. 2006 Feb 2;354(5):445-7

Procedure EMEA/COMP Legislation: orphan drug status • Europe : EMEA – COMP – Committee on orphan medicinal products – Since 2000 (Verordening (V d i (EG) 141/2000 dd 16-12-1999) 16 12 1999) – Incentives to encourage companies • • • •

Protocol assistance Financial benefits (fee reduction) Marketing exclusivity (10 years) European registration (all countries)

• • • • • •

EMEA protocol assistance Start at day 1 Study by COMP Advice COMP at day y 90 Advice tot EC Conclusion of EC – Within 30 days

• Publication – A new orphan drug is born – Not yet authorised for marketing for desired indication (other procedure)

Orphan Evolution 2001-2007 : ATC ATC/Authoristion date 2001-2004 ATC/authorisation ATC/authoristaion ATC/Autorisation date date date 2001-2007 2001-2006 2001-2003 ATC/authoristaion date 2001-2005

5%

5% 7% 5% 3%5% 2%

34% 38% 44% 40%

42% 8%

Enzyme

Antithrombotic

5% 8% 6%

Cardiac

27% 30% 33% 33% 42% 3% 2% 5% 4% 2%2% 3% 4% 7% 5% 5% 3% 5% 3% 5% 6% 8% 6% Antihypertensive

Urologic

Hypothalamic

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

0.0

•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 • If prevalence small enough … orphan h disease. di – Leukemia • Started as 1 disease • AML, CML, ALL, CLL : common known • Now 18 subtypes defined

• Mostly academic research – Subsidized by EC (EMEA)

• Small patient populations – Multinational, multicentric research – Lower level of evidence (p<0.05 ??) – Case reports >> RCT

• 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

• Existing molecule, different route – Pedea (= ibuprofen)

• Hydrea versus Siklos

– Sildenafil • 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) = NTBC = Orfadin

(€ 58 / 10 mg) (= 5,8 5 8 M€/kg)

– Remicade – Epogen

• Hydroxycarbamide – =Hydrea – =Siklos

The Orphan Drug Backlash (Scientific American May 2003:71-77)

400 x

(€ 0.1975 / 500 mg) (€ 600 / month)

• Definition of ultra-orphan drugs – Prevalence less than 0.18 / 10,000 Orphan drugs and the NHS: should we value rarity (McCabe, BMJ 2005;331:1016-1019)

The right price ?

The right price ?

• Wilzin

• • • • • •

– Zinc acetate capsules – Price € 1.25 / 50 mg g – No UD packing

• Aspirin – Acetyl salicylic acid – Price € 0.08 / 100 mg – UD packing

> 230 x price raw material

Glivec Tasigna Myozyme Aldurazyme Sprycel Savene

€ 2660 / box € 4226 / box € 556 / vial € 651 / vial € 4528 / box € 10335 / vial

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) – …

Raw materials • Orphan drugs regulated by EMEA • If producing them is not lucrative – Not available as orphan p drug g – Not available as pharmaceutical grade – Can be available as chemical grade primary material – “Orphan raw materials”

• A problem in tertiary care hospitals

Legislation • Royal Decree 19-12-1997 – Pharmacist has to use licensed materials • Magistral versus officinal preparations • Certificate of analysis

– Update 2008 (to be published) • Better quality assurance by distributor • Magistral preparations only with licensed materials

– Request to adapt the RD • Use of orphan raw materials in hospitals

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09/10/2008

Ethics versus politics

Orphan Diseases Task Force (UZL) • Survey UZL

• Phosphomannose isomerase deficiency: – A carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation – Can be treated by supplying D D-mannose mannose to the patient – Not available as brand drug nor as raw material pharmaceutical grade – Available as chemical grade substance (purity > 99.99 %) – Not allowed by law – Yet it makes the difference in quantity and quality of life Jaeken et al., A J Hum Genet 62 (1998), pp. 1535–1539

Autosomal recessive

– Over 100 orphan diseases reported – 18 orphan drugs and 11 orphan raw materials – Total budget € 7,000,000 (2007)

• Requested foundation of “Leuven coordination center for rare diseases and their treatments” – Purpose : administrative support • e.g. reimbursement by convention • Soon available: www.weesziektencentrale.be

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 • Deficiency in the enzyme alpha-galactosidase • Accumulation of a glycolipid in vessels and tissue (globotriaosylceramide) • Symptomatical treatment

– Preparation in LAF by hospital pharmacist – Started as study medication • 2 hours stable after defrosting Æ patient had to come to hospital • 8 hours stable after defrosting Æ medication transported by taxi – Less expensive as hospital admission

• Problem with aggregation during transport – Company suggests no transport – Use of particle inline filter to protect patient – Use of human albumine to buffer Æ problem solved

• 24 hours stable after preparation

• Therapy makes difference between live and dead • Unpredictable prognosis

Pulmonary arterial hypertension

– Symptoms: skin lesions, cornea verticilla, renal and cardiac complications

• Treatment by enzyme substitution – Agalsidase alpha (Replagal) – Agalsidase beta (Fabrazyme)

• Infusion every 2-3 weeks

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, oral anticoagulants, and oxygen – Prostaglandins: • Epoprostenol (Flolan (Flolan, synthetic prostacyclin) – Continuous infusion in central venous catheter – Instability (t½ = 5’) : on ice during administration

• Treprostinil (Remodulin) – IV – Oral and inhalation in developping

• Iloprost (Ilomedine) : longer t½ – IV – Inhalation : Ventavis (US)

• Beraprost (oral – Japan and Korea)

– Endothelian receptor antagonist • Bosentan (Tracleer) • Sitaxentan (Thelin)

– Phosphodiesterase inhibitors • Sildenafil (Viagra) • Sildenafil (Revatio)

– Surgery • Lung transplant

– Varia • 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 %

•Very expensive therapy •Surviving until surgery •Partially financed by BSF (limited resources / budget)

– Levodopa and carbidopa in intestinal gel – Administration by pump – Stability 15 weeks in fridge; 16 h at 40°C – € 45,000 / year / patient

Wilson disease

Wilson disease

• Autosomal recessive genetic disorder • Copper accumulates in tissues • Symptoms

• Treatment

– 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, …

– 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

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Reflections Conclusions

• Orphan drugs have a special status – Prevalence, profit, availability, legislation, …

• Orphan drugs – – – – – –

Definition depends on continent Need depends on population Status versus needs (eg raw materials) Mostly very expensive therapies Mostly live saving for a small population Pharmacist has an important role

• Similar ? – – – – –

• Advising, preparing, dispensing, reimbursement

– EMEA is supporting – Ethical discussions are possible

• “Drug orphans” versus “Orphan drugs”

Orphan drugs in Europe Geneesmiddel

ALDURAZYME ATRIANCE BUSILVEX CARBAGLU

CYSTADANE

DIACOMIT EVOLTRA EXJADE FABRAZYME GLIOLAN GLIVEC INOVELON LITAK LYSODREN MYOZYME NAGLAZYME NEXAVAR ONSENAL ORFADIN PEDEA PHOTOBARR PRIALT REPLAGAL REVATIO SAVENE SOMAVERT SPRYCEL SUTENT THELIN TRACLEER TRISENOX VENTAVIS WILZIN XAGRID

fl 500E

Vorm

vial 250 mg/50ml

Laronidase

Actieve stof

Firma Genzyme nv

Orphan drugs outside Europe Telefoon 02/714.17.10

Nelarabine

Glaxo

Busulfan

Pierre Fabre

02/556.49.90

02/522.78.98

Nee

Carglumic acid

Orphan Europe

02/461.01.36

02/461.02.36

Ja

gr poeder caps 500 mg

Betaïne Stiripentol

Orphan Europe Benelux Biocodex

02/461.01.36 00 33 141 24 30 00

02/461.02.36 00 33 141 24 30 04

Nee Nee

Fl 20 mg

Clofarabine

Quintiles

00 31 23 567 0910

00 31 23 565 78 26

Nee

tabl 125 & 250 & 500 mg fl inj 35 mg

Deferasirox Agalsidase beta

Genzyme nv

02/714.17.10

02/714.17.09

Ja

sir 30 mg/ml

5-Aminolevulinezuur

Medac

03 897.19.00

03.897.19.19

Nee

caps 100 & 400 mg

Imatinib

Novartis Pharma nv

02/246.15.15

02/246.15.00

Ja

tabl 100 mg

Rufinamide

Novartis Pharma nv

02/246.15.15

02/246.15.00

Nee

Clabridine

02/246.15.15

Lipomed

02.656.24.95

02/246.15/00

00 31 413 369 285

Nee

Ja

Nee

tabl 500 mg

Mitotaan

Laboratoire HRA Pharma

00 33 140 331 130

00 33 140 331 231

Nee

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

amp 1 mg/ml

Galsufase

Biomarin

0477/89.60.40

051/63.53.47

Nee

tabl 200 mg

Sorafenib tosylate

Bayer

02/535.65.30

02/539.00.88

Ja

caps 200 mg

Celecoxib

Pfizer

02/722.03.97

02/721.42.65

Nee

caps 10 mg

Nitisinone

Orphan Europe

02/461.01.36

02/461.02.36

amp 10 mg/2 ml

Ibuprofen

Orphan Europe Benelux

02/461.01.36

02/461.02.36

Fl 15 mg/ fl 75 mg

Porfimer sodium

Fl 100 mg/ml

Ziconotide

Ja Nee Nee

Eisai Pharma

00 44 1932 824123

00 44 1932 824323

Nee

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

tabl 20 mg

Sildenafil

Pfizer

02/722.03.97

02/721.42.65

Nee

Fl 500 mg

Dexrazoxane

Topotarget

33 1 41 27 73 45

45 39 17 98 98

Nee

amp 10mg/15 mg/ 20mg tabl 20 & 50 & 70 mg

Pegvisomant

Pfizer

02/722.03.97

02/721.42.65

Ja

Dasatinib

Bristol-Myers-Squibb

02/352.76.11

02/352.75.66

Ja

caps 12,5 & 50 mg

Sunitinib

Pfizer

02/722.03.97

02/721.42.65

caps 100 mg

Sitaxentan sodium

tabl 62,5 & 125 mg

Bosentan

Pharma Logistics

02/363.15.70

02/363.15.99

amp 10 mg/10 ml

Arsenic trioxide

Cell Therapeutics

Ja Nee Ja Ja

Iloprost

XYREM ZAVESCA

Terugbetaling? Ja

amp 6 mg

amp 10 mg/5 ml

02.656.26.01

Fax 02/714.17.09

tabl 200 mg

Novartis Pharma

Compassionate use Medical need Conventions Clinical trial Off label use (especially in pediatrics, …)

Nee

caps 25 & 50 mg

Zinc acetate

Orphan Europe Benelux

02/461.01.36

02/461.02.36

Nee

caps 0,5 mg

Anagrelide

Pharma Logistics

02/363.15.70

02/363.15.99

Ja

500 mg/ml

Sodium oxybate

UCB Pharma

02/559.92.26

tabl 100 mg

Miglustaat

Pharma Logistics

02/363.15.70

Nee 02/363.15.99

Ja

Geneesmiddel ADVATE

Vorm fl inj 5 ml 500E

ADVATE

fl inj 5 ml 1000E

BERINERT FERRIPROX FLOLAN FLOLAN

amp 500E tabl 500 mg fl IV 500 mcg fl 1,5 mg + 2x50 ml solv

HELIXATE NEXGEN

fl 250E

HELIXATE NEXGEN

fl 500E

HELIXATE NEXGEN

fl 1000E

ILOMEDINE KOGENATE

amp 0,05 mg fl 250IU

KOGENATE

fl 500IU

KOGENATE

fl 1000IU

NOVOSEVEN NOVOSEVEN NOVOSEVEN PROLASTIN PROLEUKIN PULMOZYME

4,8 mg (240KUI) 60 KUI (1,2 mg) 240 KUI (4,8 mg) fl 40 ml 1000 mg fl IV 1 mg 18 milj inhal amp 2,5 mg/2,5 ml

REFACTO

fl 500E

REFACTO

fl 1000E

REFLUDAN RILUTEK SOMATULINE SOMATULINE SOMATULINE SOMATULINE THALIDOMIDE THYROGEN

XENAZYNE

fl IV 50 mg tabl 50 mg autogel spuit inj 90 mg autogel spuit inj 60 mg autogel spuit inj 120 mg P.R. fl IM 20 mg/ml tabl 50 mg kit 2xvial 1.1 mg + 2x10 ml opl pulv. vr. inj. 0,9 mg amp opl vr neb 300 mg/5 ml tabl 25 mg

ZEFFIX

tabl 100 mg

THYROGEN TOBI

Actieve stof Octocog alfa (recombinante stollingsfactor VIII) Octocog alfa (recombinante stollingsfactor VIII) C1-esteraseremmer Deferiprone Epoprostenol Epoprostenol Octocog alfa (recombinante stollingsfactor VIII) Octocog alfa (recombinante stollingsfactor VIII) Octocog alfa (recombinante stollingsfactor VIII) Iloprost-tromethamine Octocog alfa (recombinant coagulation factor VIII) Octocog alfa (recombinant coagulation factor VIII) Octocog alfa (recombinant coagulation factor VIII) Eptacog alfa (geactiveerd) Eptacog alfa (geactiveerd) Eptacog alfa (geactiveerd) Alpha1-Proteinase Inhibitor (Human) Recombinant humaan Interleukin-2 Dornasum alfa Moroctocog alfa (recombinante coagulatiefactor VIII) Moroctocog alfa (recombinante coagulatiefactor VIII) Lepirudine Riluzole Lanreotide Lanreotide Lanreotide Lanreotide Thalidomide Thyrotropine alfa

Firma Baxter Hyland

Telefoon 02/650.18.86

Fax 02/650.18.55

Terugbetaling Ja

Baxter Hyland

02/650.18.86

02/650.18.55

Ja

ZLB Behring OPG Medico Glaxo Smith Kline nv Glaxo Smith Kline nv

016/38.80.81 00 31 102 62 57 63 02/656.26.01 02/656.26.01

016/38.80.89 00 31 102 62 57 60 02/656.24.95 02/656.24.95

Nee Ja Nee Nee

ZLB Behring

016/38.80.81

ZLB Behring

016/38.80.81

016/38.80.89

Ja

ZLB Behring

016/38.80.81

016/38.80.89

ja

Schering nv Bayer Pharma

02/712.85.00 02/535.65.39

02/725.43.00 02/539.00.88

Nee Ja

016/38.80.89

Ja

Bayer Pharma

02/535.65.39

02/539.00.88

Ja

Bayer Pharma

02/535.65.39

02/539.00.88

Ja

Novo Nordisk Novo Nordisk Novo Nordisk Bayer Pharma Red Swan pharma logistics Roche nv

02/520.62.10 02/520.62.10 02/520.62.10 02/535.65.39 02/223.33.30 02/525.82.36

02/539.00.88 02/223.34.30 02/525.82.66

Ja Ja Ja Nee Ja Ja

Wyeth Pharmaceuticals nv

010/49.48.50

010/49.46.80

Ja

Wyeth Pharmaceuticals nv

010/49.48.50

010/49.46.80

Ja

Pharma Logistics Sanofi Synthelabo nv Ipsen nv Ipsen nv Ipsen nv Ipsen nv

02/363.15.70 015/50.96.43 09/243.96.00 09/243.96.00 09/243.96.00 09/243.96.00 0800/496.84 02/714.17.10

02/363.15.99 015/50.96.60 09/220.44.73 09/220.44.73 09/220.44.73 09/220.44.73 0800/496.86 02/714.17.09

Ja Ja Ja Ja Ja Ja Ja Ja Ja Ja

Genzyme nv

Thyrotropine alfa Tobramycinum

Genzyme nv Solvay Pharma & Cie

02/714.17.10 02/422.27.11

02/714.17.09 02/422.27.99

Tetrabenazine

John Bell-Croyden

00 44 20 79 35 55 55

00 44 20 79 35 96 05

Nee

Lamivudine

Glaxo Smith Kline

02/656.26.01

02/656.24.95

Ja

Orphan-like drugs in Europe (before 2000) Geneesmiddel AMMONAPS BENEFIX

Vorm gran940mg/g; tabl500mg fl 500E

BENEFIX

fl 1000E

BEROMUN

fl IV 1 mg

CEREZYME CYSTAGON CYSTAGON ORLAAM QUADRAMET VITRAVENE

400E fl pulv. vr. inj. caps 50 mg caps 150 mg 10 mg / ml 6,6 mg/ml: 0,25 ml

Actieve stof Natriumfenylbutyraat

Firma Orphan Europe Benelux

Telefoon 02/461.01.36

Fax 02/461.02.36

Terugbetaling Nee

Nonacog alfa (recombinant coagulation factor IX) Nonacog alfa (recombinant coagulation factor IX) Tasonermine

Baxter Hyland

02/650.18.86

02/650.18.55

Ja

Imiglucerase Mercaptamine Mercaptamine Levomethadyl HCl-acetaat Samarium lexidronam pentanatrium Fomivirsen natrium

Baxter Hyland

02/650.18.86

02/650.18.55

Ja

Boehringer Ingelheim nv Genzyme nv Orphan Europe Orphan Europe

087/31.50.05

087/31.21.97

Ja

02/714.17.10 02/461.01.36 02/461.01.36

02/714.17.09 02/461.02.36 02/461.02.36

Ja Ja Nee Nee Nee Nee

Thank you for 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