Avastin, Lucentis & Zaltrap, Eylea

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

Scandal in the Media!

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

Age related macular degeneration

4th cause of blindness Leading cause of severe vision loss in industrialized courtries. Cécité. Who: third as a cause of blindness after cataract and glaucoma Refractive error: myopie, pb refraction lumiere.. Childhood: deficicit vit A Onchocerciasis: onchocercose, cecité des rivières + infection Afrique (Mectizan® de Merck) Trachoma: tracome (chlamyidose refilé de la mere à l’enfant) 2 infection en baisse continue 50 million people worldwide Proportion of cases of blindness due to each major cause (2008)

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

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

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

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

Methods to slow the wAMD disease progression
Ophtalmogy surgery Protective factors & Complements/ Medicines Laser photo coagulation therapy Photodynamic therapy (Verteporfin injections) Vitrectomy Antioxydants, mineral supplements HMG Co-A reductase inhibitor (statin) Aucun remede seulmt ralentissement de la progression Photodynamic: stabilise la perte visuelle chez la moitié des patients. injection intraveineuse de vertéporfine (vysudine), photosensibilisant, suivie de l'application d'une lumière rouge par laser sur la zone à traiter, permettant une destruction de la néovascularisation. (radicaux oxygen) Medicines : Recombiant monoclonal antibody

Wet AMD : physiopathology
1- Stress of epithelial tissu anticorps monoclonaux recombinants, ciblés contre le facteur de croissance endothéliale de type A VEDF: facteur important dans la neovascularisation En se liant a ses recepteurs, le VEGF‑A active la proliferation et la migration des cellules endotheliales choriocapillaires des vaisseaux. Ses isoformes, qui se differencient notamment en fonction de leur affi nite pour l’heparine de la matrice extracellulaire, peuvent se lier aux recepteurs tyrosine kinase 2- 3- = Angiogenesis Mechanism

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

Potential targets: VEGF A / PIGF
4 isoforms VEGF A: more active in angiogenesis PIGF Placenta Growth Factor + nouvelle cible pr nouvelle association: PDGF R Beta Existe pls isoformes A Tous role dans angiogenese

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

Anti VEGF marketed PEGAPTANIB (MACUGEN): First Anti Angiogenic Agen
28 Base RNA Aptamer Selectively binds extra cellular VEGF 165 Pegaptanib, which binds to VEGF165 and longer isoforms, ranibizumab and bevacizumab, which bind all VEGF-A isoforms, and aflibercept, which binds VEGF-A, VEGF-B, and placental growth factor, all bind VEGF165 with high affinity.

Avastin & Lucentis

Avastin / Lucentis Mechanism of action

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 (clinically : Graefe's Archive for Clinical and Experimental Ophthalmology February 2014, Volume 252, Issue 2, pp , Pharmacokinetics of bevacizumab after topical and intravitreal administration in human eyes, Elad Moisseiev et al), 5.6 days (calculated :Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor Trap-eye)

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

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

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

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.

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

Off-Label Use

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 The marketing authorisation holder has not investigated and tested all potential applications of the product concerned These tests and clinical trials are very expensive and their outcome is uncertain. The applicant may decide to focus on one aspect of the product in view of the pressure on pharmaceutical companies to speed up the marketing of new medicines. The benefits of registration do not outweigh the costs because, for instance, the application concerns a rare disease. Ethical, legal and/or practical reasons make it more complicated or not feasible to carry out the clinical trials (for example, clinical trials in children or in pregnant or lactating women). The applicant may not have been aware of the feasibility to apply the active substance for a specific treatment. The producer of a medicinal product has investigated and tested a certain application of the product, but nonetheless decides against registering it. By not registering the application, the producer aims to avoid (product) liability claims for damage that occurs in that application. The producer has no incentive to register the application, because: registration of the additional application would generate little or no additional sales, given that the product is already being used for the application concerned (albeit off-label); or a different medicinal product of the same producer is already indicated for the same application.

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.

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 Is publicly known : NCCN

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)

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

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

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

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

Off-label Use European Position for Avastin/Lucentis
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 NICE has included off-label recommendations Several sickness funds have entered into agreements with doctors’ associations which provide financial incentives to use off-label medicines LFSS 2013 and economic RTU

EFPIA position paper : Promotion of off-label use of medicines by European healthcare bodies in indications where authorised medicines are available November 2011 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 Healthcare bodies in some European countries have begun promoting off-label use of medicines in indications where there are already approved medicines available : 2. 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 bypasses and indeed undermines the rigorous regulatory approval process, which is designed to ensure patient safety. It raises serious concerns over patient safety as it is promoting the use of medicines in indications for which the competent regulatory authorities have not performed a risk-benefit analysis following established safety and efficacy criteria.  Promotion of off-label use by healthcare bodies also creates legal uncertainty associated with product liability, in particular the question of who would be accountable for safety issues associated with the off-label use.  There are additional practical concerns as to how the new information generated by non-industry funded clinical trials would be disseminated (if not in the summary of the product characteristics (SPC) or patient information leaflet (PIL)) or updated (e.g. reacting to adverse event reporting). In many countries other information sources, e.g., websites, derive patient information from the official PILs. If non-regulatory authorities, governmental agencies and HTA/ cost- effectiveness bodies such as NICE, promote off-label use of medicinal products, the position and authority of the competent regulatory authorities at EU and national level is undermined. Ultimately, it could lead to double standards for medicines and thus compromise patient safety and public health. 3. Promotion of off-label use by healthcare bodies sets double standards  Promotion of off-label use by healthcare bodies gives rise to the impression that these bodies may have the discretion to override the regulatory approval process.  On the other hand companies that try to expand use of an approved medicine through off-label use promotion are rightly threatened with heavy sanctions.  Government agencies have the right to assess the value of new and existing medicines and to fund clinical trials where companies have not carried out direct comparisons. In order to maintain the same regulatory standards and not to compromise patient safety, clinical trials on off-label uses should meet the same criteria as those sponsored by companies, including trial design and statistical plans. The results must be analysed under the same regulatory standards that review submissions from companies.

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

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

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

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!

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

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

Eylea mechanism of action

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

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.

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.

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

Mean change in visual acuity

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.

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?

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

What price for Eylea treatment?

AMD Arena in numbers Global net sales: $4,2 billion by 06/2013
Patent expiration in 2016 Top reimbursed drug en ville in France with: €390 million in 2012 U.S. sales in 2013: 6,254 billion CHF, ($ 7,006 billion) +13% Sales growth VS 2012 at constant exchange rates 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 Worldwide net sales $70 million in 2013 Launches in Eurxope following approval in February 2013

Reimbursement of Lucentis® in UK
Favorable NICE Recommendation BUT treatment not to exceed 14 injections Novartis lowers cost-effectiveness ratio Additional injections free Risk-sharing agreement Path: Manufaturer propose a file / price and justifies it. NICE makes Favorable recommendation from NICE for funding on the basis that it was cost-effective, but was limited to a course of treatment not to exceed 14 injections of Lucentis. To avoid this limitation, Novartis agreed to pay for any injections of Lucentis that exceeded the 14 recommended by NICE, thereby making the additional injections free to both the patient and health care system * Ce sont des injections qui sont free, mais le reste des frais de tratement repose sur la NHS The approach helped to protect Lucentis’ place in the market and ensure that patients could continue their treatment. It also had the advantage of a lower overall cost to the NHS for the improved outcome, thus lowering its cost-effectiveness ratio and making it more attractive for adoption.

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

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 Health outcomes-based risk-sharing agreements Payers and manufacturers share the risk of developing and paying for a new technology Growing Trend in Europe and North America Health outcomes linked to payments ensures that patients and payers are getting the most value possible for their money by only paying for what works pharmaceutical manufacturers are able to enter a marketplace while proving their drug’s value in real world settings. In the absence of long term data, payment and reimbursement schemes will continue to become more popular among those paying for new technologies Intro to risk sharing: Consumers and payers for health care products and services are increasingly demanding evidence of treatment benefits and are basing decisions on comparative evidence of effectiveness, as opposed to relying solely on evidence derived from a placebo-based trial or analysis. Payers need to have a means to assess a drug’s value in terms of health outcomes ♦♦(effectiveness) and expense (costs). In case of insufficient evidence on relative effectiveness or incremental cost-effectiveness, payers ♦♦have turned to novel approaches that base reimbursement on the eventual outcome realized. Health outcomes linked to payments ensures that patients and payers are getting the most value possible for their money by only paying for what works; Patient Access Schemes Drugs which receive a positive NICE appraisal, that have a PAS scheme attached, are commissioned on the basis that any PAS is fully utilised and adhered to. When assessing new drugs and treatments - to decide whether they represent good value for the NHS - NICE looks at evidence on how well the treatment works compared with available alternatives, and the cost of treatment. Drugs or treatments that are expensive and do not have a significant benefit over existing treatments are unlikely to be approved by NICE for use in the NHS. Patient access schemes are special ways Pharmaceutical companies can propose to enable patients to gain access to high costs drugs. Where a patient access scheme exists it is vital that NHS bodies make full access to the scheme to secure maximum cost effectiveness of providing treatment. Each scheme is different and hence a good understanding of them will ensure they are used to their full potential.

Risk-sharing Schemes Worldwide
Lucentis, on est la United BioSource Corporation, Coulton L1, Annemans L2, Javier J3, Brown R3, Keskinaslan A4

Reimbursement of Eylea & Zaltrap
Country Reimbursment USA Yes Australia Japan Switwerland Germany UK France Rest of UE Pending Quelle est la situation actuelle au niveau de remimburesement, d’Eylea et le compagnone Zaltrap don’t la question d’utilisation off-label dans la meme indication de DMLA se pose? EYLEA U.S. Patient Assistance. There are several options available to help patients with the cost of EYLEA : Uninsured Patients may be eligible to receive EYLEA at no cost under the EYLEA4U® Patient Assistance Program Underinsured Patients Not Covered by a State or Federal Healthcare Program may qualify for assistance with their out-of-pocket co-pay costs through the EYLEA4U® Co-Pay Program Underinsured Patients Enrolled in a State or Federal Healthcare Programs may be referred to independent, non-profit organizations that help patients with their out-of-pocket treatment costs

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. Reimbursement of Eylea® in UK To get a positive recomendation by NICE… When NICE recommends a treatment 'as an option', the NHS must make sure it is available within the period set out in the paragraph above. Including a confidential discount offered by Bayer, NICE noted that the incremental cost of Eylea was estimated to be £12,300 per QALY gained compared with dexamethasone and that, even in the worst case scenario, the cost fell within the range that would normally be considered a cost-effective use of NHS resources The list price of aflibercept 40 mg/ml solution for injection is £816 per vial The Department of Health and the manufacturer have agreed that aflibercept solution for injection will be available to the NHS with a patient access scheme which makes aflibercept solution for injection available with a discount. The size of the discount is commercial in confidence. Cost-effectiveness results aflibercept dominated ranibizumab because it resulted in lower costs and higher quality-adjusted life years (QALYs; 7.77 compared with 7.76) When the manufacturer applied a discount to the list price of ranibizumab, ranging from 10 to 50%, aflibercept continued to dominate ranibizumab. aflibercept dominated (that is, was less expensive and more effective than) ranibizumab

Pricing Eylea Point of view of the manufacturer
Point of view of the Health Care Provider Marginal costs of manufacturing Research & Development Marketing Meeting regulatory requirements Drug acquisition costs Administration costs Monitoring costs Managing adverse events 1. Manufacturer sets the average wholesale price (AWP), of their new drug. It is commonly assumed that the manufacturer indexes their drug’s price to be some profit margin above the variable costs of development, production and distribution, marketing and meeting regulatory manufacturing requirements. 2. The drug acquisition costs -> incorporated the confidential discount applied to the list price of aflibercept approved as part of the patient access scheme. The same for the Lucentis -> a discount to ranibizumab for all indications At the time of submission for this appraisal, the manufacturer of aflibercept was unaware of the size of the confidential discount and therefore presented a range of scenario analyses, which applied discounts to the list price of ranibizumab ranging from 10% to 50% 2. The resource use and unit costs associated with treatment and monitoring visits were based on Hospital Episode Statistics (HES 2010/11) and NHSreference costs (2011/12). L’achat, les frais liees a l’adminitration, le suivi When assessing new drugs and treatments - to decide whether they represent good value for the NHS - NICE looks at evidence on how well the treatment works compared with available alternatives, and the cost of treatment.

Costs associated with blindness When treated with Lucentis
Low-vision aids Rehabilitation Residential care District nursing Community care Cost of treating complications like depression and falls /hip replacement In total =£6067 in the first year and = £5936 in subsequent years The total cost applied was £6067 in the first year and £5936 in subsequent years. The costs related to sight impairment for patients treated with Lucentis are around £8000 cheaper than for patients who receive best supportive care over a 10 year period. The Committee heard from the patient experts that visual impairment has a substantial negative impact on the physical and emotional wellbeing of people with wet age-related macular degeneration. The patient experts stated that the condition affects their ability to work and other leisure activities and in turn, can increase the risk of depression and social isolation. The patient experts also acknowledged that, despite any initial anxiety about having an injection in the eye, they are willing to receive injections in order to prevent sight loss. The Committee agreed that loss of vision caused by wet age-related macular degeneration can substantially impair health-related quality of life. Andrew Dillon, NICE Chief Executive, said: ”Lucentis is an expensive drug, costing more than £10,000 for each eye treated. But that cost needs to be balanced against the likely cost savings. AMD results in reduced quality of life and increased risks of illness, particularly in relation to accidents – especially falls – and psychological ill-health. Studies have also demonstrated that patients with visual impairment tend to have longer hospitalisations, make greater use of health and community care services and are more likely to be admitted to nursing homes. It has been estimated that the costs related to sight impairment for patients treated with Lucentis are around £8000 cheaper than for patients who receive best supportive care over a 10 year period. Our guidance means that patients who are suitable for this treatment will have the same access to it, irrespective of where they live.” Costs associated with blindness When treated with Lucentis = £8000 saving over a 10 year period * study of blindness in the UK that focused on people with age-related macular degeneration (Meads and Hyde 2003)

Pricing Eylea Tretment Administration and monitoring £257,45 per visit Price per dose Fluorescein angiogrphie = £117 No cost of adverse effects + + + = Assistance per visit = £90 Les memes demarches que le labo a utilise dans odbrani Eylea dossier apred de NICE Voir les demarches Calculer Because of the low incidence of adverse events reported in the VIEW 1 and 2 studies, the manufacturer did not apply the costs of adverse events in the base-case analysis. An important advantage of aflibercept is that it needs less frequent administration than ranibizumab while achieving similar clinical outcomes, as seen in the clinical trials, thus imposing less burden on NHS capacity. Aflibercept is also associated with fewer treatment and monitoring visits, it will reduce the burden on patients and their carers in terms of travel costs and time off work. The clinical specialists explained that people treated with ranibizumab and bevacizumab should have their condition monitored every 4 weeks and that very few NHS trusts were able to manage wet age-related macular degeneration at such regular intervals. The Committee considered the manufacturer's decision to exclude bevacizumab for intravitreal use as a comparator in its submission, despite being listed as a comparator in the scope. It was aware that bevacizumab does not have a UK marketing authorisation for treating wet age-related macular degeneration. However, the Committee noted that a marketing authorisation is not a prerequisite for a comparator in a NICE technology appraisal. It noted that NICE's Guide to the methods of technology appraisal, in recommending comparison with technologies that are 'best practice' or in 'routine use', is not intended to be restrictive but to emphasise the need for comparison with all relevant comparators; any medicine in routine use or considered to be best practice should be considered a potential comparator. + + +

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 £816 per dose £761,20 per dose = £13 510 £8 352 =

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

Pricing in France Lucentis ASMR II Eylea ASMR V Pour repondre a la question du debut : quelle prix pour Eylea? …. Ces conventions garantissent pour les médicaments d’ASMR de niveau I à III, sur une période de 5 ans à compter de leur première mise à disposition aux patients par leur inscription au remboursement en ville ou à l’hôpital, que le niveau de prix ne sera pas inférieur au prix le plus bas parmi ceux pratiqués sur les 4 principaux marchés européens comparables (l’Allemagne, l’Espagne, l’Italie et le Royaume-Uni). la fixation de ce prix tient compte principalement de l’amélioration du service médical rendu apporté par le médicament, des prix des médicaments à même visée thérapeutique, des volumes de vente prévus ou constatés, ainsi que des conditions prévisibles et réelles d’utilisation du médicamen À l’instar de ce qui s’est passé aux États-Unis, l’arrivée prochaine d’Eylea® (afl ibercept) sur le marché français va rompre la situation quasi monopolistique de Lucentis® dans la prise en charge médicamenteuse de la dégénérescence maculaire liée à l’âge (DMLA) par des spécialités disposant d’autorisation de mise sur le marché (AMM). Compte tenu de l’ASMR V (amélioration du service médical rendu de niveau V) attribuée à Eylea®, son inscription au remboursement doit engendrer, conformément au code de la Sécurité sociale, une économie dans le coût du traitement de la DMLA. L’Assurance Maladie estime donc que le contexte impose une baisse signifi cative du prix du Lucentis® et une fi xation du prix d’Eylea® à un niveau permettant effectivement des économies dans le coût du traitement de la DMLA. « Si c’est pas mieux c’est moins cher, si c’est mieux c’est peut être plus cher » Mr Teisseire

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.

Thank you for your attention
Any questions? Thank you for your attention

Sources blindness / Nature NICE guidance WHO website Sante.gov, ameli.fr FDA website, EMA website EFPIA website European comission HAS website Bayer website AMD ressource center

Avastin, Lucentis & Zaltrap, Eylea

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Avastin, Lucentis & Zaltrap, Eylea

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