hi

1. +
Avastin, Lucentis &
Zaltrap, Eylea
Romain Boidin, Julie Trolle, Amirouche Brahimi,
Sonja Nektarijevic, Anne Bodin

2. +
Scandal in the Media!
2

3. +
Summary
 Age related macular degeneration
 Avastin and Lucentis
 Off-label Use
 Two new players : Eylea and Zaltrap
 Intravitreal Use of Zaltrap?
 What price for Eylea treatment?
 Conclusion
3

4. +
Age related macular
degeneration

5. +
4th cause of blindness
Leading cause of
severe vision loss in
industrialized
courtries.
Proportion of cases of blindness due to each major cause (2008)
50 million people
worldwide
5

6. +
Risk factors & prevalence
Age >50y,
20% of 65-75y
Smoking Heredity Genetic Nutrition
High blood
pressure
Sunlight
overexposure
Race:
Caucasien
Gender:
Femmes
6

7. +
Clinical symptoms
 It first, affected one eye
 The blurring of the central vision:
 distortion of central vision
 blind spots
 central scotomas
 Loss of contrast sensitivity
 Forms alteration
 Hallucinations
 Blindness
 Quality of life:
 Difficult to read, difficulty recognising people's faces
 Anxiety
 Locomotion difficulties, autonomia
7

8. +
Diagnosis & view measures
 Visual acuity test VAC
 Eye fundus (dilated eye exam)
 Amsler grid
 Fluorescein angiogram
 Optical coherence tomography OCT
8

9. +
Macula degeneration, 2 forms
 Dry AMD
 cellular debris
called drusens accumulates between
the retina and the choroid
 Macula light-sensitive cells slowly
deteriorate
 Visual impairment
 Wet AMD
 Abnormal blood vessels grow up
from the choroid behind the retina
 Aggressive and faster progression
 Blindness
Wet
AMD
20%
Dry
AMD
80%
9

10. +
Methods to slow the wAMD disease
progression
 Laser photo coagulation therapy
 Photodynamic therapy (Verteporfin
injections)
 Vitrectomy
 Antioxydants, mineral supplements
 HMG Co-A reductase inhibitor
(statin)
Ophtalmogy surgery
Protective factors & Complements/
Medicines
Medicines : Recombiant monoclonal antibody
10

11. +
Wet AMD : physiopathology
1- Stress of epithelial tissu
2-
3-
= Angiogenesis Mechanism
11

12. +
Anti-VEGF : mechanism of action
 Intravitreal injection
 Receptor mimetism: Catching of VEGF
 Inhibition of angiogenesis
 Reduction of fluid and exsudats
12

13. +
Potential targets: VEGF A / PIGF
4 isoforms
VEGF A: more active in angiogenesis
PIGF Placenta Growth
Factor
13

14. +
Double action of VEGF
Macula
neovascularization
Tumor Angiogenesis:
Colon tumor, ovarian
14

15. +
Anti VEGF marketed
15

16. +
Avastin & Lucentis

17. +
Avastin / Lucentis Mechanism of action
17

18. +
Lucentis & Avastin
Brand name
Indication
Wet forms of macular degeneration
Macular oedema
Choroidal neovascularisation
Metastatic colorectal cancer; Metastatic
breast cancer; Advanced, metastatic or
recurrent non-small-cell lung cancer;
Advanced or metastatic kidney cancer;
Cancer of the ovary
Molecule Ranibizumab Bevacizumab
Half-Life
Plasmatic : 0,5 days
Intravitreal : 3.2 days (calculated)
Plasmatic : 21 days
Intravitreal : 4.9 days
Price
France : 895,57€
USA : 1950$
France : 278 €
USA (March 2013) : 50$
Company
18

19. +
The development of anti-VEGF
compounds
1989
Genentech first
isolates VEGF
1993
mAbs targeting VEGF slow
down tumor growth
1997
Beginning of the development of Avastin
2002
First results of anti-VEGF therapy in
macular degeneration1
June 2005
1st publications showing efficacy of Avastin in
AMD
(1)Preclinical and phase
1A clinical evaluation of
an anti-VEGF pegylated
aptamer (EYE001) for
the treatment
ofexudative AMD.
Eyetech Group study.
Retina. 2002
February 2004
FDA approves Avastin
January 2005
EMA approves Avastin
June 2006
FDA approves Lucentis
January 2007
EMA approves Lucentis
19

20. +
Comparative studies
Funding Methods Endpoint Results
CATT (2011) American NIH
multicenter, single-
blind, non-
inferiority,
randomized
visual acuity after 1
year
Avastin and
Lucentis had
equivalent effects
IVAN (2012) UK
multicenter, non-
inferiority,
randomized
best corrected
distance visual
acuity at 2 years
Lucentis and
Avastin have
similar efficacy
GEFAL (2013)
Programme
Hospitalier de
Recherche
Clinique National
2008
multicenter, non-
inferiority, double
masked,
randomized
mean change in
visual acuity at 1
year
Avastin was non
inferior to Lucentis
20

21. +
Reconditioning Avastin
 Avastin 25mg/mL 16mL : 278€
 DMLA : 0.5mg per injection
 Risk of infection
 High risk injection to begin with
 Reconditioning increases the risk of introducing germs
 The reconditioning was done by hospitals, pharmacies, or the practitioners
themselves
 In August 2011, the FDA sends out an alert after clusters of Streptococcus
endophthalmitis infections.
 All were linking to the same pharmacy.
 The legal frame being progressively built around this practice could improve
the quality and safety of the preparations
21

22. +
Reconditioning Avastin
Serious adverse events
Is intravitreal Avastin causing more cardiovascular side effects than Lucentis?
 Some meta-studies have suggested that intravitreal Avastin may cause more
arterial thrombotic events.
 CATT, IVAN and GEFAL :
 Did not show any significant difference in side effects between the
treatments
 However, none of these studies had the statistical power to detect rare
side effects
 These were randomized clinical trials in a controlled environment
 Is there a socio-economical effect?
 No socialized medicine = disparities in patients
The patients being given Avastin are not from the same socioeconomic
background as the ones receiving Lucentis.
22

23. +
Is Lucentis overpriced?
 Price of a drug ≠ cost of production.
 The price rewards innovative research by being set based on the benefit
brought to patients and society.
 Was giving such a high price to Lucentis a mistake? Was the size of the target
population underestimated?
 The controversy over Lucentis and Avastin illustrates the collision of two
divergent philosophies :
 Industrials and governments basing prices on cost/benefit studies
 Practitioners and patients who see the possibility of just dividing Avastin
in several injections to be able to afford it
23

24. +
Off-Label Use

25. +
Off-label Use Background
 The marketing authorisation holder has not investigated and tested all potential
applications of the product concerned
 The producer of a medicinal product has investigated and tested a certain
application of the product, but nonetheless decides against registering it.
 Off-label use may be induced by the government
25

26. +
Off-label Use European legislation :
definition
 Guideline on good pharmacovigilance practices, Annex I : off-label use
 Situations where a medicinal product is intentionally used for a medical
purpose not in accordance with the authorised product information.
26

27. +
Off-label Use European legislation
Pharmaceutical industry liability
 Did they knew or should have known of the off-label use?
 How?
 Is publicly known (ex : congress)
 Takes place on a large scale
 Is extensively documented
 Accounts for a significant percentage of the medicinal product’s sales
 Was reasonably foreseeable
27

28. +
Off-label Use European legislation
Pharmaceutical industry liability
 Impact of the pharmacovigilance directive 2010/84/CE and regulation No
1235/2010
 Adverse reaction :
 « Ensure that it covers noxious and unintended effects resulting not only
from the authorised use of a medicinal product at normal doses, but also
from medication errors and uses outside the terms of the marketing
authorisation, including the misuse and abuse of the medicinal product »
 Reporting of any use of the medicinal product which is outside the terms of
the marketing authorisation
 Member States have to put in place a pharmacovigilance system
 Eudravigilance database (centralised medicines)
28

29. +
Off-label Use European legislation
Pharmaceutical industry liability
 Warn about the risks of off-label use
 Through SmPC and/or package leaflet
 Risk Management plan : post autorisation off-label use (SV.4)
 Module XV of EMA’s Guideline on Good pharmacovigilance practices
 Direct healthcare professional communication
 Press releases
 Messages on the marketing autorisation holder’s website
 Messages disseminated through other internet tools
29

30. +
Off-label Use European legislation
Ex : Roche liability for Avastin
30

31. + Off-label Use European legislation
Physicians and pharmacists liabilities
 Physicians liability
 Enhanced (article 5, 2001/83/EC)
 Off-label prescribing should better serve the patient’s needs than “on-label”
prescription of an alternative medicine.
 Off-label prescribing should have a solid scientific basis.
 The prescribing physician should obtain the patient’s explicit consent to off-
label use (informed consent requirement).
 The prescribing physician should keep clear, accurate and legible records of
all medicines prescribed, the reasons for prescribing them and their (side)
effects.
 Pharmacists liability
 Practical application is complicated, a pharmacist often being unaware that a
medicine was prescribed off-label
31

32. +
Off-label Use European legislation
Physicians and pharmacists liabilities
 Examples of Risks in France :
 Disciplinary liability
 Civil liability
 Penal liability
32

33. +
Off-label Use European Position for
Avastin/Lucentis
NICE has included off-label
recommendations
Clinical trials sponsored by healthcare bodies
comparing approved medicines with off-label
medicines was being held in 5 European countries :
The cheaper off-label medicine against the approved
treatment
Several sickness funds have entered into
agreements with doctors’ associations
which provide financial incentives to use off-
label medicines
LFSS 2013 and economic RTU
33

34. +
Off-label Use European Position for
Avastin/Lucentis
 Decisions on off-label medicine use should remain in the hands of the treating
physician and be taken on the basis of the medical need of the individual patient
 Medicines may not be promoted for unlicensed uses (Art. 87 of Directive
2001/83/EC).
 Priority to be given to protection of public health over economic considerations
 Promotion of off-label use by healthcare bodies may compromise patient safety
and creates legal uncertainty with regard to product liability
 Promotion of off-label use by healthcare bodies sets double standards
EFPIA position paper : Promotion of off-label use of medicines by European
healthcare bodies in indications where authorised medicines are available
November 2011
34

35. +
Off-label Use European Position for
Avastin/Lucentis
Decision of the European Court of Justice (Fourth Chamber)
11 April 2013
Activities such as those at issue in the main proceedings, provided that they do not result in a modification of the medicinal
product concerned and are carried out solely on the basis of individual prescriptions calling for processes of such a kind – a
matter which falls to be determined by the referring court –, do not require a marketing authorisation under Article 3(1) of
Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community
procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a
European Medicines Agency, but remain, in any event, subject to Directive 2001/83/EC of the European Parliament and of
the Council of 6 November 2001 on the Community code relating to medicinal products for human use, as amended by
Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010.
Do not result in a modification of the medicinal product concerned and are carried out solely
on the basis of individual prescriptions calling for processes of such a kind do not require a
marketing authorisation
35

36. +
Off-label Use American legislation
 American guidances about unapproved indications for marketed
medicinal products :
 Postmarketing Safety Reporting for Human Drug and Biological Products
Including VaccinesRelated laws
 Special report situation : unapproved indication
 "Off-Label" and Investigational Use Of Marketed Drugs, Biologics, and
Medical Devices - Information Sheet
 Physicians have the responsibility to be well informed about the product,
to base its use on firm scientific rationale and on sound medical evidence,
and to maintain records of the product's use and effects
 Does not require IND
 Responding to Unsolicited Requests for Off-Label Information About
Prescription Drugs and Medical Devices
36

37. +
Off-label Use American legislation
Ex : Roche liability for Avastin
37

38. +
Off-label Use American Position for
Avastin/Lucentis
 Medicare and Medicaid take charge of both medicines, Avastin and Lucentis
for AMD
 Speeding-up the procedure of authorization of new applications:
 Largely in response to pressures from patient groups eager to have
potentially life-saving drugs available as quickly as possible, FDA has
instituted “accelerated approval,”
 Major limitation: agency cannot act on drugs for which supplemental
applications are not submitted!
38

39. +
Two new players :
Eylea and Zaltrap
The story
repeat it
self!

40. +
Eylea & Zaltrap approvals
November 2011
FDA approves Eylea for wet
AMD (Regeneron )
November 2012
Eylea has been approved by the EC for
the treatment of patients with wet AMD.
(Bayer Healthcare)
August 2012
the FDA approves Zaltrap (ziv-aflibercept)
February 2013
EC has granted MA in the European
Union for ZALTRAP 25mg/ml (Sanofi &
Regeneron)
40

41. +
Eylea mechanism of action
EYLEA
41

42. +
Eylea & Zaltrap
Brand
name
Indication
Neovascular (Wet) Age-Related
Macular Degeneration (AMD)
Macular Edema Following Central
Retinal Vein Occlusion (CRVO)
Indicated for patients with metastatic
colorectal cancer (mCRC) resistant to or
has progressed following an oxaliplatin-
containing regimen
In combination with + 5-fluorouracil,
leucovorin, irinotecan (FOLFIRI)
Molecule Aflibercept Ziv-Aflibercept
Dosing
Forms
2 mg (0.05 mL)/ 4 weeks , 8 weeks
Only for intravitreal injection
4 mg/kg as an intravenous infusion over
1 hour / 2 weeks
Price France : 810,12 € TTC France : 313,86 € HT
Company
42

43. +
Eylea (VEGF trap eye)
 First year: 7 treatment visits, 7 injections of Eylea (2mg /injection)
 Second year: frequency of visits and injections depends on anatomical and
visual results of the first year.
43

44. +
Clinical studies
 VIEW 1 and VIEW 2
 Clinical trials: Phase 3 (pivotal)
 Non inferiority study
 Study of the Efficacy, Safety of Repeated Doses of Intravitreal VEGF Trap in
Subjects with wet AMD
 The two biggest cohorts of people studied to date in wet AMD
 Including almost 2,500 patients and more than 360 sites worldwide.
44

45. +
View1 & View2 studies
Studies design
Two Randomized, Double Masked, Active Controlled, multi-
center phase 3 studies.
Patient
enrolment
View1: n= 1217, in USA and Canada
View2: n= 1240, in Europe, Asia Pacific, Japan and Latin
America
Patient ages ranged from 49 to 99 years with a mean of 76
years.
Interventions
• VEGF Trap-Eye dosed 0.5 mg / Every 4 weeks
• VEGF Trap-Eye dosed 2 mg / Every 4 weeks
• VEGF Trap-Eye dosed 2 mg / Every 8 weeks
• Lucentis dosed 0.5 mg / Every 4 weeks
Endpoints
• Primary: prevention of moderate vision loss (loss of >=15
letters) at one year. (week 52 compared to baseline).
• Secondary: best-corrected ETDRS visual acuity at one year
45

46. +
Mean change in visual acuity
http://performances-medicales.com/ophta/encours/192/03.pdf
46

47. +
Results of view1 & view2
 Treatment with Aflibercept produced equivalent efficacy and safety outcomes
as Lucentis.
 Generally favorable safety profile
 These studies demonstrate that Aflibercept is an effective treatment for wet
AMD,
 Every-2-month regimen offering the potential to reduce the risk from
monthly intravitreal injections and the burden of monthly monitoring.
47

48. +
Could Zaltrap be used instead of Eylea?
 Is there a real risk to see Zaltrap being used off-label?
 There is already a well-known option used off-label in AMD : Avastin
 As a second line treatment after Avastin?
48

49. +
Could Zaltrap be used instead of Eylea?
 Can this use be limited?
 Zaltrap's SmPC in Europe :
 Osmolarity of Zaltrap : 1000 mOsmol/kg ;
 Osmolarity of an eye : 300 mOsmol/kg
 Volume to inject to achieve the right dose : 2mg -> 80µL
1 ml/40 mg of aflibercept
1ml/25 mg of aflibercept
49

50. +
What price for Eylea
treatment?

51. +
AMD Arena in numbers
 Global net sales: $4,2
billion by 06/2013
 Patent expiration in 2016
 Top reimbursed drug en
ville in France with: €390
million in 2012
 In Top 5 most successful
new products launches
in biopharma industry
 Global net sales 2013:
$1.881 billion
 Expected to grab 16% of
the market from Lucentis
 U.S. sales in 2013:
6,254 billion CHF, ($
7,006 billion)
 +13% Sales growth VS
2012 at constant
exchange rates
 Worldwide net sales
$70 million in 2013
 Launches in Eurxope
following approval in
February 2013
51

52. +
AMD Arena in numbers
 Global net sales: $4,2
billion by 06/2013
 Patent expiration in 2016
 Top reimbursed drug en
ville in France with: €390
million in 2012
 In Top 5 most successful
new products launches
in biopharma industry
 Global net sales 2013:
$1.881 billion
 Expected to grab 16% of
the market from Lucentis
 U.S. sales in 2013:
6,254 billion CHF, ($
7,006 billion)
 +13% Sales growth VS
2012 at constant
exchange rates
 Worldwide net sales
$70 million in 2013
 Launches in Eurxope
following approval in
February 2013
52

53. +
AMD Arena in numbers
 Global net sales: $4,2
billion by 06/2013
 Patent expiration in 2016
 Top reimbursed drug en
ville in France with: €390
million in 2012
 In Top 5 most successful
new products launches
in biopharma industry
 Global net sales 2013:
$1.881 billion
 Expected to grab 16% of
the market from Lucentis
 U.S. sales in 2013:
6,254 billion CHF, ($
7,006 billion)
 +13% Sales growth VS
2012 at constant
exchange rates
 Worldwide net sales
$70 million in 2013
 Launches in Eurxope
following approval in
February 2013
53

54. +
Reimbursement of Lucentis® in UK
Risk-sharing agreement
Novartis lowers cost-effectiveness ratio
Additional injections free
BUT treatment not to exceed 14 injections
Favorable NICE Recommendation
54

55. +
Reimbursement of Lucentis® in UK
Risk-sharing agreement
Novartis lowers cost-effectiveness ratio
Additional injections free
BUT treatment not to exceed 14 injections
Favorable NICE Recommendation
55

56. +
Reimbursement of Lucentis® in UK
Risk-sharing agreement
Novartis lowers cost-effectiveness ratio
Additional injections free
BUT treatment not to exceed 14 injections
Favorable NICE Recommendation
56

57. +
Reimbursement of Lucentis® in UK
Risk-sharing agreement
Novartis lowers cost-effectiveness ratio
Additional injections free
BUT treatment not to exceed 14 injections
Favorable NICE Recommendation
57

58. +
Reimbursement of Lucentis® in UK
Risk-sharing agreement
Novartis lowers cost-effectiveness ratio
Additional injections free
BUT treatment not to exceed 14 injections
Favorable NICE Recommendation
58

59. +
What is a risk-sharing agreement?
 Any conditional reimbursement:
 Patient access schemes
 Value-based pricing
 Risk-sharing agreements
 Pay-for-outcomes
 Performance-based pricing
 Coverage with evidence development
Finance based
Price discounts, e.g. in the shape
of:
Outcome based
• Dose cap
• Limited number of
patients
• Free initial stock
• Initial discount
• Return of treatment/drug
cost in case of failure
• Delayed reimbursement
after proven response
59

60. +
Risk-sharing Schemes Worldwide
United BioSource Corporation, Coulton L1, Annemans L2, Javier J3, Brown R3, Keskinaslan A4
60

61. +
Reimbursement of Eylea & Zaltrap
Country Reimbursment
USA
Yes
Australia
Japan
Switwerland
Germany
UK
France
USA
Yes
France
Rest of UE Pending
61

62. +
Pricing Eylea
 Eylea It is very expensive. A typical fill can cost $1,972 or more for 1 kit of
2mg/0.05ml Eylea.
 Eylea demonstrating efficacy on a par with Lucentis, but needing to be dosed
less frequently (half as often; on paper at least)
 Eylea has not only assumed market share at the expense of Lucentis, but also
off-label Avastin, which is available at a significantly cheaper cost of around
$50 per injection (some 37-times cheaper than Eylea)
 Eylea & Lucentis : The manufacturer has agreed a patient access scheme with
the Department of Health which involves a confidential discount applied to the
list price of aflibercept solution for injection. The level of the discount is
commercial in confidence.
62

63. +
Pricing Eylea
 Marginal costs of manufacturing
 Research & Development
 Marketing
 Meeting regulatory requirements
 Drug acquisition costs
 Administration costs
 Monitoring costs
 Managing adverse events
Point of view of the manufacturer
Point of view of the Health Care
Provider
63

64. +
 Low-vision aids
 Rehabilitation
 Residential care
 District nursing
 Community care
 Cost of treating complications like depression
and falls /hip replacement
Costs
associated with
blindness
When treated with Lucentis
= £8000 saving over a
10 year period
In total
=£6067 in the first
year and
= £5936 in
subsequent years
* study of blindness in the UK that focused on people with age-related macular degeneration (Meads and Hyde 2003)

65. +
Pricing Eylea
=
+ +
No cost of
adverse effects
+
+ + +
Price per
dose
Tretment
Administration and
monitoring £257,45
per visit
Fluorescein angiogrphie
= £117
Assistance per
visit
= £90
65

66. +
First year of treatment: one-stop model
Month
1
2
3
4
5
6
7
8
9
10
11
12
Month
1
2
3
4
5
6
7
8
9
10
11
12
£761,20 per dose
£816 per dose
= £13 510 £8 352 =
66

67. +
Total treatment prices
for 1 year treatment
£ 13 510 ($22,660) £8 352 ($14,018)
Of which £18,300 Lucentis Of which £9,000 Eylea
DISCOUNT
67

68. +
Pricing in France
 Lucentis
 ASMR II
 Eylea
 ASMR V
« Si c’est pas mieux c’est moins cher, si c’est mieux c’est peut être plus
cher »
Mr Teisseire
68

69. +
Conclusion
 Innovation is still in march, new products with new targets are in the pipeline. A
new drug is going to be associated with Eylea. What price to give it?
 Should we give priority to cost over Health?
 What role for the governments in cost-effectiveness related decisions?
 What role should patients have in the decisions?
 This episode constitutes a precedent of off-label use of a very similar
compound for economic reasons.
69

70. +
Thank you for your
attention
Any
questions?

71. +
Sources
 www.cehjournal.org/article/changing-patterns-in-global-blindness-
1988-2008/
 Nature
 NICE guidance
 WHO website
 Sante.gov, ameli.fr
 FDA website, EMA website
 EFPIA website
 European comission
 HAS website
 Bayer website
 AMD ressource center
71