Orphan Drugs Doctoral Seminar

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Today (9th October 2008), here is PhD seminar on Orphan drugs. Let’s have a look on what the term orphan exactly refers to, when used in context to Drugs and Disease.

Transcript of Orphan Drugs Doctoral Seminar


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

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

Definition: Orphan disease The term orphan disease implies two separate but related concepts. To describe diseases that are overlooked by doctors, and has been applied, applied for example to Fabry's disease alveolar echinococcosis variant example, Fabry s disease, echinococcosis, 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).Aronson, Br J Clin Pharmacol. 2006 March; 61(3): 243245

Definition: Orphan disease Prevalence less than USA Japan Australia Europe WHO : 1/200,000 : 1/50,000 : 1/2,000 : 5/10,000 : 6.5-10/10,000Aronson, Br J Clin Pharmacol. 2006 March; 61(3): 243245

Definition: Orphan disease 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

Definition of orphan drugs

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 Americanswww.fda.gov , accessed 29-09-2008

Affecting 6-8 % of the population (EU : 25 million patients)



Where do they come from ? Intentionally developed (eg Tasigna) Unintentionally developed (eg Thalidomide)

Legislation: orphan drug status USA : Orphan drug act (ODA) Since January 1983 Incentives to encourage companies Tax reductions Extended marketing exclusivity (+ 7 years)

Target g


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

Success ? 83 04 : 250 drugs authorised 73 83 : 10 such drugs on marketHaffner, 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 (V d i (EG) 141/2000 dd 16 12 1999) (Verordening 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 90 y 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 : ATCATC/Authoristion date 2001-2003 ATC/authorisation datedate2001-2004 ATC/authoristaion date 2001-2006 ATC/Autorisation 2001-2007 ATC/authoristaion date 2001-2005

5% 34% 38% 44% 40%

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

42% 8% 5% 8% 6%

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 Antineoplastic Immunosuppressive Analgesic Antihypertensive Antiepileptica Other Antineoplastic Enzyme Enzyme Antithrombotic Antithrombotic Cardiac Antihypertensive Hypothalamic Hypothalamic Antineoplastic

It started with enzymetherapy Shift toward antineoplastic drugs



Authorisation per administration route

Prevalence Prevalence/10.0004.0 3.5



3.0 2.5 2.0 1.5 1.0 0.5

Oraal Parenteraal


No specialised administration necessary in all cases. Treatment in ambulatory care is possible.

slicing to orphan diseases Possible to slice a disease into types If prevalence small enough orphan di h disease. Leukemia Started as 1 disease AML, CML, ALL, CLL : common known Now 18 subtypes defined Different types recognized as orphan disease and treated with orphan drugs (eg. chloretazine, oxaliplatin, ) USAY. Waknine, 2004

Rocket science at high cost ? Mostly academic research Subsidized by EC (EMEA)

Small patient populations Multinational, multicentric research Lower level of evidence (p> RCT

Financial risk when not protected

Rocket science at high cost ? High-tech synthetisation Enzymes : Aldurazyme, Myozyme,

Rocket science at high cost ? Simple molecule, same administration Wilzin (= zinc acetate capsules) Treatment of Wilsons disease

Older products, new name Thalidomide (Softenon)

Existing product, different name Hydroxycarbamide Hydrea versus Siklos

Existing molecule, different route Pedea (= ibuprofen)

Sildenafil Viagra versus Revatio



The right price ?

The right price ?

Very expensive therapies-pharmacokinetic challenge to calculate cost-utility (QALYs) ?

Can raise ethical questions-EMEA states that every citizen has the right to receive healthcare.(Maastricht treaty, December 1991)

The right price ? Nitisinone : herbicide (low price)= NTBC = Orfadin ( 58 / 10 mg) (= 5 8 M/kg) 5,8400 x

The right price ? From orphan to blockbuster Remicade EpogenThe Orphan Drug Backlash (Scientific American May 2003:71-77)

Hydroxycarbamide =Hydrea =Siklos ( 0.1975 / 500 mg) ( 600 / month)

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

The right price ? Wilzin Zinc acetate capsules Price 1.25 / 50 mg g No UD packing

The right price ? Glivec Tasigna Myozyme Aldurazyme Sprycel Savene 2660 / box 4226 / box 556 / vial 651 / vial 4528 / box 10335 / vial

Aspirin Acetyl salicylic acid Price 0.08 / 100 mg UD packing

> 230 x price raw material

Who will/can pay ?



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 drug p g Not available as pharmaceutical grade Can be available as chemical grade primary material Orphan raw materials

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

A problem in tertiary care hospitals

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



Ethics versus politics Phosphomannose isomerase deficiency: A carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation Can be treated by supplying D-mannose to the patient D mannose 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 lifeJaeken et al., A J Hum Genet 62 (1998), pp. 15351539

Orphan Diseases Task Force (UZL) Survey UZL 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

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.



Pompe disease Therapy Alfa-glucosidase Recombinant human enzyme Replaces the missing enzyme Breaks down glycogen.

Prolongs ventilator-free survival and overall survival ventilator free 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 Preparation by pharmacist Preparation in LAF by hospital pharmacist Started as