Orphan drugs and haemophilia

Flora Peyvandi MD, PhD
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center,
Fondazione IR...
Rare disorders

• Are a group of very different diseases, whose common
denominator is that they are low-prevalence disease...
Orphan Drugs

• Because of the rarity, the cost of developing and
marketing a medicinal product to diagnose, treat or
prev...
Regulation of Orphan drug was adopted:

USA
(Introduction of the US
Orphan Drug Act)

Japan
(Orphan Drug
Regulation)

1983...
Orphan drug designation in Europe

The European Medicines Agency (EMA), through its
Committee for Orphan Medicinal Product...
Annual number of orphan drug designation and
marketing (2000-2010)
European Union:
• 684 designated orphan drugs
• 63 rece...
Orphan drugs designation and obtaining
marketing approval

• The EU Orphan Drug regulation is highly appreciated
for its r...
Orphan drugs
• The development of orphan drugs is stimulated through a
number of regulatory and economic incentives

• The...
Marketing exclusivity

USA
7 years

European Community
10 years

Japan
10 years

Australia
5 years
Orphan Medicinal Products
EC regulation 141/2000

Article 8(1) - 10 years market exclusivity:
for 10 years after granting ...
EC regulation 141/2000 on
Orphan Medicinal Products
Article 8(3) describes three types of derogations from the
market excl...
Market exclusivity and Hemophilia

Flora Peyvandi
Orphan designation

A medicine must meet a number of criteria to qualify for
orphan designation:

http://www.ema.europa.eu...
Haemophilia
is the most frequent inherited coagulation disorders due to
the deficiency of FVIII (haemophilia A) and FIX (h...
Haemophilia

• is X-linked recessive blood coagulation disorder

• associated with bleeding episodes affecting soft tissue...
New drugs for hemophilia

could be qualified as “orphan drugs”

and, as orphan drugs, could benefit from economic
incentiv...
Market Exclusivity

Key Concepts
• Significant Benefit
• Definition of a similar product

Flora Peyvandi
Market exclusivity and Hemophilia

If satisfactory treatment exist the
sponsor should establish that the
product will be o...
Haemophilia care
• substantial improvements during the past 40–50 years
• advent of recombinant concentrates, has greatly
...
CURRENT HEMOPHILIA THERAPY
Very safe and very effective but….
COST
Immunogenic
Neutralizing antibodies in
30% of severe he...
Greater safety and
reduced
immunogenicity

Enhanced efficacy
Prolongation of the half-life

Flora Peyvandi

Lower cost wit...
Extension
of half-life

PEGylation
Chemical coupling of
polyethylene glycol (PEG),
increased hydrodynamic volume
to preven...
X
Prematurely
stopped due to an
increased number of
bleeding events

Flora Peyvandi

Suspended - A multiple dose phase 1b
...
Pre-clinical

Phase I

Phase II

Phase III

BAX855

Ongoing

BAY94-9027

Ongoing

N8-GP

Market

Ongoing

rFVIIIFc

Comple...
Results of Long acting products
- Clinical studies -

Factor IX

Factor VIII

1.5 to 1.6-fold

rFVIIa

Flora Peyvandi

3 t...
Market Exclusivity

• The Haemophilia community welcome all of these
approaches
• Not clear which of these will result in ...
Definition of a similar product
Based on the definitions set out in Article 3 of Regulation
847/2000, the assessment of si...
FVIII & FIX Long-acting
Are they similar products?
• Different recombinant proteins
• Different cells
• Different PEG mole...
• EHC Position communicated to EMA :
“Orphan drug designation should not be
used to hinder the development, licensing
and ...
Currently, the requirements for the preregistration
and postregistration assessment of safety and
efficacy for new product...
Harmonization of efficacy and safety
(EMA vs FDA)
• Numbers and types of subjects
100 PTPs with hemophilia A or 40 PTPs wi...
Harmonization EMA - FDA
• The discrepancy between EMA and FDA implies a severe
disadvantage for European patients, because...
Conclusion

• Haemophilia patients benefit from a large number of
plasma-derived and recombinant

products however

furthe...
Conclusion

• Orphan drug designation and market exclusivity
should be considered only for those coagulation
disorders wit...
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Orphan Drugs and Haemophilia by Flora Peyvandi

  1. 1. Orphan drugs and haemophilia Flora Peyvandi MD, PhD Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and University of Milan Italy EUROPEAN HAEMOPHILIA CONSORTIUM 26th Annual Conference 4 – 6 October 2013, Bucharest, Romania
  2. 2. Rare disorders • Are a group of very different diseases, whose common denominator is that they are low-prevalence diseases • The current estimate of rare disorders is 6000 to 8000 and 80% have a genetic origin and affect children at a very early age • In the US a disease that affects less than 200,000 inhabitants • In the EU, besides affecting fewer than 5 per 10.000 inhabitants, a rare disease needs to be life threatening or chronically debilitating Flora Peyvandi
  3. 3. Orphan Drugs • Because of the rarity, the cost of developing and marketing a medicinal product to diagnose, treat or prevent a rare condition would not be recovered by the expected sales of the medicinal product under normal market conditions • Therefore, in several jurisdictions specific legislation has been introduced to stimulate the development of drugs for a rare diseases, so-called “orphan drugs” Flora Peyvandi
  4. 4. Regulation of Orphan drug was adopted: USA (Introduction of the US Orphan Drug Act) Japan (Orphan Drug Regulation) 1983 1982 1993 1990 Australia (Orphan Drug Policy) 1998 2000 European Union (Regulation Number 141/2000 of the European Parliament and the Council) Flora Peyvandi 2010
  5. 5. Orphan drug designation in Europe The European Medicines Agency (EMA), through its Committee for Orphan Medicinal Products (COMP), is responsible for reviewing designation applications from persons or companies who intend to develop medicines for rare diseases, known as ‘orphan medicines’ Flora Peyvandi
  6. 6. Annual number of orphan drug designation and marketing (2000-2010) European Union: • 684 designated orphan drugs • 63 received marketing approval Distribution of orphan drug marketing authorizations by therapeutic area. Flora Peyvandi
  7. 7. Orphan drugs designation and obtaining marketing approval • The EU Orphan Drug regulation is highly appreciated for its role in creating a favorable orphan drug development environment • However, this apparent success of the legislations has also been questioned Flora Peyvandi
  8. 8. Orphan drugs • The development of orphan drugs is stimulated through a number of regulatory and economic incentives • These incentive measures can be broken down into three types:  Marketing exclusivity of the orphan drug, whereby sponsors of this drug are granted a given period of marketing exclusivity during which no other drug will be approved for the disease in question  the setting up of tax credits and research aids  simplification of and advantages in the drugs authorization procedure Flora Peyvandi
  9. 9. Marketing exclusivity USA 7 years European Community 10 years Japan 10 years Australia 5 years
  10. 10. Orphan Medicinal Products EC regulation 141/2000 Article 8(1) - 10 years market exclusivity: for 10 years after granting of a marketing authorization (approval for sale), orphan medicinal products benefit from market exclusivity in the EU. During this period, directly competitive similar products cannot normally be placed on the market Flora Peyvandi
  11. 11. EC regulation 141/2000 on Orphan Medicinal Products Article 8(3) describes three types of derogations from the market exclusivity provided under Article 8(1) of that Regulation: (a) consent of the original marketing authorisation holder (b) inability of the original marketing authorisation holder to supply sufficient quantities (c) the second medicinal product is safer, more effective or otherwise clinically superior Flora Peyvandi
  12. 12. Market exclusivity and Hemophilia Flora Peyvandi
  13. 13. Orphan designation A medicine must meet a number of criteria to qualify for orphan designation: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp Flora Peyvandi
  14. 14. Haemophilia is the most frequent inherited coagulation disorders due to the deficiency of FVIII (haemophilia A) and FIX (haemophilia B) - 1 in 5,000 is born with haemophilia type A - 1 in 30,000 is born with haemophilia type B
  15. 15. Haemophilia • is X-linked recessive blood coagulation disorder • associated with bleeding episodes affecting soft tissue, joints and muscles • repeated haemorrhages result in chronic arthropathy, with loss of joint movement, fixed flexion contracture, and severe muscle wasting Flora Peyvandi
  16. 16. New drugs for hemophilia could be qualified as “orphan drugs” and, as orphan drugs, could benefit from economic incentives including market of exclusivity (10 years) Could market exclusivity potentially create a monopoly rather than market competition to ensure the widest possible access at the most affordable price? Flora Peyvandi
  17. 17. Market Exclusivity Key Concepts • Significant Benefit • Definition of a similar product Flora Peyvandi
  18. 18. Market exclusivity and Hemophilia If satisfactory treatment exist the sponsor should establish that the product will be of significant benefit Flora Peyvandi
  19. 19. Haemophilia care • substantial improvements during the past 40–50 years • advent of recombinant concentrates, has greatly improved the safety and availability of therapy FVIII cloning FIX cloning Refacto Kogenate Recombinate Benefix Recombinant 4th generation Long-acting Advate 1982 1990 2000 2010 2003 – Recombinant 3th generation 2000 – Recombinant 2nd generation 1997 – Recombinant FIX 1992 – Recombinant 1st generation Flora Peyvandi
  20. 20. CURRENT HEMOPHILIA THERAPY Very safe and very effective but…. COST Immunogenic Neutralizing antibodies in 30% of severe hemophilia A and up to 3% of hemophilia B patients Frequent injections Prophylactic regimens: infusion 2–3 times weekly Flora Peyvandi Problems of hemophilia care No available products
  21. 21. Greater safety and reduced immunogenicity Enhanced efficacy Prolongation of the half-life Flora Peyvandi Lower cost with improved delivery Challenges for new hemophilia products Greater and wider coagulation factor availability
  22. 22. Extension of half-life PEGylation Chemical coupling of polyethylene glycol (PEG), increased hydrodynamic volume to prevent clearance by kidney Albumin fusion Fc fusion Fc fragment and albumin have the same unique mode to recycling through the FcRn ligands at the endothelial cell surface to increase the half-life Albumin PEG (40kDa) Flora Peyvandi IgG-Fc
  23. 23. X Prematurely stopped due to an increased number of bleeding events Flora Peyvandi Suspended - A multiple dose phase 1b trial has been paused in order to allow further assessment of non-clinical data prior to proceeding into higher dose cohorts.
  24. 24. Pre-clinical Phase I Phase II Phase III BAX855 Ongoing BAY94-9027 Ongoing N8-GP Market Ongoing rFVIIIFc Completed May 2013, the FDA has accepted the the marketing approval of ELOCTATE N9-GP Ongoing rIXFP (CSL654) Ongoing rFIXFc Completed March 2013, the FDA has accepted the marketing approval of ALPROLIX rVIIaFP (CSL689) Flora Peyvandi Completed
  25. 25. Results of Long acting products - Clinical studies - Factor IX Factor VIII 1.5 to 1.6-fold rFVIIa Flora Peyvandi 3 to 5-fold 2 to 3-fold
  26. 26. Market Exclusivity • The Haemophilia community welcome all of these approaches • Not clear which of these will result in best clinical outcomes in long term • Need different approaches and competition Flora Peyvandi
  27. 27. Definition of a similar product Based on the definitions set out in Article 3 of Regulation 847/2000, the assessment of similarity between two medicinal products under Article 8 of Regulation (EC) No 141/2000 takes into consideration: 1. Principal molecular structural features 2. Mechanism of action and therapeutic indication If significant differences exist within one or more of these criteria, then the two products will be considered as not similar. Flora Peyvandi
  28. 28. FVIII & FIX Long-acting Are they similar products? • Different recombinant proteins • Different cells • Different PEG molecules (different sizes) linked to the protein • Different fusion proteins (Fc, Albumin) Flora Peyvandi
  29. 29. • EHC Position communicated to EMA : “Orphan drug designation should not be used to hinder the development, licensing and marketing of other products for the same condition which have demonstrably different protein modification or enhancement. Flora Peyvandi Brian O’ Mahony June 2013
  30. 30. Currently, the requirements for the preregistration and postregistration assessment of safety and efficacy for new products differ between the two major regulatory agencies for biologics – the Food and Drug Administration (FDA) in the USA and the European Medicines Agency (EMA) in the European Union (EU). Flora Peyvandi
  31. 31. Harmonization of efficacy and safety (EMA vs FDA) • Numbers and types of subjects 100 PTPs with hemophilia A or 40 PTPs with hemophilia B 50 PTPs (age ≥12 years) 50 PTPs (age 6- <12 years) 20 PTPs (age ≥12 years) 20 PTPs (age 6- <12 years) FDA 80 PTPs not require pediatric trials EMA guidelines require studies in children Flora Peyvandi
  32. 32. Harmonization EMA - FDA • The discrepancy between EMA and FDA implies a severe disadvantage for European patients, because they have to wait for data stemming from studies involving children • The lack of harmonization will increase the disparity in the treatment of patients with haemophilia • European patients will not have access to new products at the same time as patients in the US and other regions of the world. Flora Peyvandi
  33. 33. Conclusion • Haemophilia patients benefit from a large number of plasma-derived and recombinant products however further improvement is required to extend the half-life of products and reduce their immunogenicity • These products differ in structure (cDNA, vectors, cells) and could not be considered similar Flora Peyvandi
  34. 34. Conclusion • Orphan drug designation and market exclusivity should be considered only for those coagulation disorders with no available products deficiency Flora Peyvandi as FV
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