Download Aflibercept for the treatment of wet age

London New Drugs Group
APC/DTC Briefing Document
Aflibercept (Eylea®) for wet age-related macular degeneration
March 2013
Summary
Aflibercept (Eylea®) is a recombinant fusion protein which binds to and inhibits activation of vascular endothelial
growth factor (VEGF-A) and Placental Growth Factor (PIGF) receptors, and is approved for use in the EU to treat
adults with wet age related macular degeneration (AMD).
Aflibercept has been evaluated for the treatment of wet AMD in two large studies against the current therapy
recommended by NICE, ranibizumab. It was demonstrated that intravitreal aflibercept (every two months after
three consecutive monthly doses) was non-inferior to monthly intravitreal ranibizumab at 52 weeks with the
possibility that effectiveness continues for up to 2 years with as needed dosing. Efficacy beyond two years will be
established with longer term studies which are still on-going.
Aflibercept offers an alternative treatment option in the UK to existing NICE approved treatment ranibizumab.
Clinical evidence in those patients who require frequent retreatment or have failed previous therapy with
ranibizumab is limited as patients receiving prior treatment for wet AMD were excluded from the licensing trials.
Benefits postulated for aflibercept over ranibizumab include reduced frequency of drug administration and
monitoring (see critical evaluation for further discussion).
Aflibercept is competitively priced in comparison to ranibizumab (first year cost, £5712 vs. £5937, based on 8
injections per year). However, this depends on the frequency of ranibizumab injections used which will vary in
individual localities. In addition as confidential patient access schemes exist for both drugs, actual cost of the
injections to various healthcare organisations may vary.
A NICE technology appraisal for aflibercept in wet AMD is expected in August 2013 which will better determine its
place in therapy and cost effectiveness.
1. Background and introduction
Age-related macular degeneration (AMD) is a progressive chronic disease of the central retina (the macula) and the
most common cause of visual impairment in individuals over the age of 55 years in developed countries (1, 2).
Approximately 85% of cases are geographic atrophy (dry) AMD and the remaining 15% of patients suffer from the more
aggressive neovascular (wet) form (3). There are about 26,000 new cases of wet AMD in the UK each year and the
condition affects more women than men (4). In wet AMD, a process called choroidal neovascularisation occurs, which is
growth of new blood vessels that result in blood and protein leakage. The seepage and scarring from these blood vessels
eventually causes irreversible damage to photoreceptors and can lead to vision loss (5). Vascular endothelial growth
factor (VEGF) has been shown to be elevated in patients with wet AMD and is thought to play a key role in the
neovascularisation process (5,6).
Two anti-VEGF preparations, pegaptanib and ranibizumab, have UK marketing authorisation and have been subject to a
single NICE technology appraisal (4). Ranibizumab is approved for treatment within specific criteria; pegaptanib is not
(4). In addition some limited use of (intravitreal) bevacizumab outside its marketing authorisation has occurred,
although whether this is a safe intervention supported by an evidence-base is contentious. Bevacizumab use is also
potentially difficult to justify given the presence of a NICE-approved option (7).
Aflibercept (Eylea®) is a recombinant fusion protein which binds to and inhibits activation of VEGF-A and Placental
Growth Factor (PIGF) receptors, resulting in suppression of VEGF-regulated stimulation of blood vessel formation and
growth (neovascularisation). It is approved for intravitreal use in the EU to treat adults with wet AMD. The
recommended treatment regimen consists of a loading phase of one injection (2mg) per month for three consecutive
doses, followed by one injection every two months thereafter. After 12 months of treatment, the treatment interval is
extended to ‘as needed’ dosing based on visual and anatomical outcomes as determined by the treating physician (8).
2. Proposed place in therapy
Ranibizumab is currently the NICE approved treatment for wet-AMD. Bayer Healthcare propose the following
advantages of aflibercept compared with monthly ranibizumab:
Eased pressure on NHS ophthalmology AMD services from fewer treatment and monitoring visits
Lower costs to the NHS in treating and monitoring patients in their first year of treatment at the range of acquisition
costs assumed
Improved patient convenience and costs to patients resulting from fewer ophthalmology clinical visits (9)
3. Evidence selected for inclusion
The pivotal phase 3 studies for aflibercept in wet-AMD were VIEW 1 (n=1217) and VIEW 2 (n=1240), which were large
multi-centre non-inferiority studies of similar design conducted over 96 weeks. Both double-blind, randomised active
controlled studies compared the efficacy and safety of aflibercept with monthly ranibizumab in patients with wet AMD
over 1 year. Further follow-up was conducted up to 96 weeks in patients receiving as needed dosing from week 52 (12).
VIEW 1 was conducted in the US and Canada and VIEW 2 in Europe, Middle East, Asia-Pacific and Latin America. An
open-label extension study of the VIEW studies is on-going (11).
In both VIEW studies patients were randomised to one of four groups: intravitreal aflibercept 0.5mg monthly (0.5q4);
2mg monthly (2q4); the licensed treatment regimen of 2mg every 2 months after three initial monthly doses (2q8); or
ranibizumab 0.5mg monthly (Rq4). The primary endpoint was non-inferiority (margin of 10%) of the aflibercept regimens
to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on ETDRS chart; per
protocol data set). Non-inferiority was shown for all aflibercept groups compared with monthly ranibizumab (95.1%,
95.9%, and 95.1% respectively for 2q4, 0.5q4, and 2q8 regimens in VIEW 1; 95.6%, 96.3% and 95.6% in VIEW 2; and
94.4% for monthly ranibizumab in both studies). Further analysis of the data was conducted to show therapeutic
equivalence as well as non-inferiority; the pre-specified 5% margin for therapeutic equivalence was met for all groups of
aflibercept showing equivalence to monthly ranibizumab (10).
As all aflibercept groups demonstrated non-inferiority to ranibizumab additional key comparisons of secondary
endpoints were conducted to test for superiority. Mean changes in best corrected visual acuity (BCVA) from baseline to
52-week were found to be similar with all treatments, although only the aflibercept 2q4 group in the VIEW 1 study was
statistically superior to ranibizumab, with a gain of +10.9 versus +8.1 letters (p=0.005) (10). After week 52, all treatment
groups were dosed as needed which was at least quarterly with more frequent dosing allowed based on predetermined
re-treatment criteria. At week 96, for those initially randomised to 0.5mg ranibizumab every 4 weeks, an average of
16.5 injections were given and those randomised to the licensed aflibercept regimen, an average of 11.2 injections were
given. Visual improvements achieved at week 52 were maintained through week 96; 92% of patients maintained visual
acuity (loss of <15 ETDRS letters) with BCVA gain of 7.9 and 7.6 letters, with aflibercept and ranibizumab respectively
(12).
4. Critical evaluation
4.1 Clinical application
Aflibercept has been evaluated for the treatment of wet AMD in two large studies against the current therapy
recommended by NICE, ranibizumab. It was demonstrated that the licensed aflibercept dosing regimen of 3 initial
monthly doses followed by 2mg every 2 months was non-inferior to monthly ranibizumab at 52 weeks. Hence the
data currently supports aflibercept used 8 weekly for up to one year, with the possibility that effectiveness continues
for up to 2 years with ‘as needed’ dosing. Efficacy beyond two years will be established with longer term studies
which are still on-going.
Aflibercept offers an alternative treatment option in the UK to existing NICE approved treatment ranibizumab. The
NICE approved criteria for the use of ranibizumab, based on study inclusion criteria, is for patients with BCVA
between 6/12 and 6/96, with no permanent structural damage to the central fovea, total lesion size < 12 disc areas
and evidence of recent disease progression (4). The aflibercept trials included a similar group of patients; those with
wet-AMD and BCVA between 6/12 and 6/96 and total lesion size < 12 disc areas, although patients with choroidal
neovascularisation affecting less than 50% of total lesion size were excluded (9,10).
The efficacy of aflibercept in patients who have previously failed on ranibizumab is limited. Small retrospective case
series have reported some benefit of switching to aflibercept after suboptimal response to other anti-VEGF agents,
including ranibizumab, although conclusions were often based on surrogate endpoints rather than improvement in
visual outcomes and after single injection use (11). In the aflibercept licensing studies, patients who had received
prior treatment for wet AMD were excluded and hence there is no good clinical evidence on the use aflibercept in
such patients (10).
4.2 Safety
The safety of aflibercept 2mg (the licensed dosing regimen) has been evaluated in 1223 patients and was generally
well tolerated and systemic non-ocular adverse and ocular related adverse effects including serious ocular effects
were similar to those for monthly ranibizumab. The most commonly reported side-effects were conjunctival
haemorrhage (26.7%), eye pain (10.3%), vitreous detachment (8.4%), cataract (7.9%), vitreous floaters (7.6%) and
increased intraocular pressure (7.2%) (8). There were few ocular injection-related adverse effects in the study eye
and data from the studies showed a rate of events/1000 injections of 1.1, 0.8, 0.1 and 0.2 for ranibizumab 0.5q4,
aflibercept 2q4, 0.5q4 and 2q8 groups, respectively. There is a theoretical risk of arterial thromboembolic events
following intravitreal use of VEGF inhibitors; the incidence was 3.3% with aflibercept vs. 3.2% with ranibizumab in
the VIEW studies, suggesting no association with an increased risk of thromboembolic events with aflibercept (8). It
is estimated that after intravitreal administration of 2mg aflibercept to patients, the mean maximum plasma
concentration of free aflibercept is more than 100 fold lower than the concentration of aflibercept required to halfmaximally bind systemic VEGF and hence systemic pharmacodynamic effects are unlikely (10).
4.3 Potential advantages and disadvantages over existing technologies
4.3.1 Convenience
Ranibizumab is administered in an outpatient or day case setting as will aflibercept. Treatment with aflibercept is
proposed to require patients to attend fewer ophthalmology clinical visits for treatment. Administration of
aflibercept within the licensed dosing would require 7 injections in the first year and 4 injections in the second year
according to limited 96 week data from the VIEW studies, although aflibercept is licensed to be used up to six times
per year after the first year (9,12). Based on NICE cost modelling for ranibizumab, patients receive a mean of 8
injections in the first year followed by a mean of 6 injections in the second year although it was noted that
ranibizumab is licensed to be used up to twelve times per year (4). Therefore, in the first year patients receiving
aflibercept would receive one fewer injection compared to ranibizumab. Beyond the first year, there is some
suggestion that reduced frequency of injections will be required with aflibercept compared to ranibizumab
although further data or use of aflibercept in clinical practice will better define the frequency of injections required
to maintain vision. More recent data from specialist centres around the UK indicate lower ranibizumab dosing
frequencies are being used than suggested by the NICE TA; 6 injections in the first year and 3 injections in the
second year (15). Individual localities should check their local ranibizumab usage for more accurate comparative
data.
The other proposed advantage with aflibercept is reduced clinic visits for monitoring visual acuity. A total of seven
monitoring visits are recommended in the first year with aflibercept which would take place during appointments
for drug administration (9). Beyond the first year the schedule for aflibercept monitoring would be determined by
the treating physician and may be more frequent than the scheduled injections (8). For ranibizumab, the
manufacturers recommend monthly monitoring and hence 12 visits would be expected over a year but in practice
there is suggestion that monitoring intervals may be extended to 6 weeks after the initial loading phase of
ranibizumab (9,15). Therefore some additional clinic appointments, depending on local policy, would be expected
over the scheduled clinic visits for drug administration.
4.3.2 Drug cost
The costs associated with wet AMD treatment and subsequent monitoring are high. The following table considers
only drug costs for the first two years and does not include administration, out-patient and monitoring costs.
Table 1: Drug costs for aflibercept and ranibizumab (13)
st
Basic NHS
Cost for 1
Cost per year
st
Cost per
year
after 1 year
vial
Aflibercept
2mg vial =
7 vials* =
4-6 vials* =
£816
£5712
£3264-4896
Ranibizumab
2.3mg vial = 8 vials* =
6 injections* =
(NICE data)
£742.17
£5937. 36
£4453.02
*Frequency of injections are based on information from the VIEW trials/
manufacturer data for aflibercept; NICE TA for ranibizumab (see further
discussion under section 4.3.1 convenience)
The costs listed above are the basic cost to the NHS however as patient access schemes exist for both ranibizumab
and aflibercept, it becomes difficult to determine actual cost savings. These prices are available to NHS
organisations upon request from Bayer Healthcare and Novartis Pharmaceuticals (ranibizumab). With regards to
the frequency of injections, Individual localities should check their local ranibizumab usage to allow a more
accurate comparative.
4.3.3. Healthcare resource utilisation
Eased pressure on NHS ophthalmology AMD services from fewer treatment and monitoring visits are proposed
advantages of aflibercept over ranibizumab. As discussed under patient convenience, patients receiving aflibercept
would be expected to receive one fewer injection in the first year compared to ranibizumab but beyond that it is
difficult to accurately estimate frequency of drug that will be required to maintain vision. With regards to
monitoring, in the first year of treatment, patients receiving aflibercept do not require to attend any additional
appointment to scheduled visits for drug administration in comparison to ranibizumab for which patients will
require one additional appointment to the scheduled visits. Beyond the first year additional monitoring may be
required to the schedule of aflibercept injections. Therefore, some benefit with regards to resource utilisation is
likely in the first year with the use of aflibercept over ranibizumab but it is difficult to determine likely benefit
beyond the initial year.
4.3.4
Suitability for shared care
Not suitable for shared care as aflibercept has to be administered by a trained specialist.
4.3.5
Likely budgetary impact
See Appendix 1
5. Likely commissioning and funding pathway
Aflibercept is expected to be funded and commissioned by Clinical Commissioning Groups.
6. Suggested place in therapy
Aflibercept will provide another option to existing ranibizumab for clinicians treating wet AMD and in particular for
newly diagnosed patients. It is unlikely to be used in patients who are stable and adequately managed with ranibizumab.
A NICE technology appraisal for aflibercept in wet AMD is expected in August 2013 which will better determine its place
in therapy and cost effectiveness.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Lim LS, Mitchell P, Seddon JM et al. Ophthalmology 1: age-related macular degeneration. Lancet 2012; 379: 17281738.
Coleman HR, Chan CC, Ferris FL et al. Age-related macular degeneration. Lancet 2008; 372: 1835- 1845.
Augustin AJ. Development in the understanding and treatment of retinal disease. Clinical Practice 2012; 9 (2): 149-152.
NICE TA 155. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. August 2008.
www.nice.org.uk
Mousa SA, Mousa SS. Current status of vascular endothelial growth factor inhibition in age-related macular
degeneration. Biodrugs 2010; 24 (3): 183-194.
Dixon JA, Oliver SCN, Olsen JL. VEGF trap-eye for the treatment of neovascular age-related macular degeneration.
Expert Opinion 2009; 18 (10): 1573- 1580.
North East Treatment Advisory Group (NETAG). Bevacizumab (Avastin®) in the management of neovascular age-related
macular degeneration: updated appraisal. July 2011.
Summary of Product Characteristics. Eylea 40mg/ml solution for injection in a vial. Bayer Healthcare Ltd. Date of
revision of the text: 22/11/2012.
Budget holder notification. VEGF-Trap-Eye (aflibercept solution for injection) for the treatment of neovascular (wet)
age-related macular degeneration (AMD). July 2011.
Heier JS, Brown DM, Chong V et al. Intraviteal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration.
American Academy of Ophthalmology 2012; 119: 2537-2548.
Personal communication. Bayer Healthcare Ltd. August 2012 & December 2012.
Heier JS. 96 weeks results from the VIEW 1 and VIEW 2 studies: intravitreal aflibercept injection versus ranibizumab for
neovascular AMD shows sustained improvement in visual acuity. Poster # 6962, session number 501. Thursday May
2012.
MIMS. March 2013. www.mims.co.uk
Economic evaluation of aflibercept solution for injection (Eylea) for the treatment of neovascular (wet) age-related
macular degeneration (AMD). Bayer Healthcare. January 2013.
Personal communication. Novartis Pharmaceuticals. March 2013.
Produced by the London New Drugs Group. Correspondence to Varinder Rai, Principal MI Pharmacist, London Medicines
Information Centre, Northwick Park Hospital, Watford Road, Harrow, Middlesex. HA1 3UJ. e-mail: [email protected]
This document reflects the views of the LNDG and may not reflect those of the reviewers. The LNDG would like to thank
[Kristin Chapman, Formulary and antibiotic pharmacist, Moorfields Eye Hospital] for their comments on this review. Bayer
Healthcare have commented on this review. Accessed via www.evidence.nhs.uk
Appendix 1 (14)
Economic evaluation provided by Bayer Healthcare
Drug, administration and monitoring cost PER EYE PER YEAR
Injections
Year 1
Cost per
eye
Difference
Aflibercept
7
£7,514.15
Cost saving
Ranibizumab
8
£7,996.96
+£482.81
Monitoring
Year 1
Aflibercept
7 total (no
additional
visits)
Ranibizumab
12 total (8
separate
visits)
Cost per eye
Difference
Difference
over 2 years
4
£4,293.80
Cost saving
Cost saving
6
£5,997.72
+£1,703.92
+£2,186.73
£318.96
visits
Cost saving
Cost saving
£717.66
visits
+£398.70
(visits)
+£1,036.62
(visits)
£1,055.34
OCT
+586.30
(OCT)
+£1,524.38
Year 2
Year 2
£0
Cost saving
£637.92
visit
+637.92
(visits)
£938.08
OCT
+938.08 (OCT)
6 total (4
separate
visits)
£469.04 OCT
12 total (9
separate
visits)
Aflibercept vial £816; Ranibizumab vial £742.17; Administration cost £257.45; Visual acuity visit £79.74; OCT 117.26
Drug, administration and monitoring cost PER 100,000 population over TWO YEARS
Injections
Year 1
Difference
per eye
Year 2
Difference
per eye
Per 100,000 –
new patients
only years 1
and 2
Additional costs per
100,000 for
continuing patients
year 2 (85%=29)
Aflibercept
7
Cost saving
4
Cost saving
Cost saving
Cost saving
Ranibizumab
8
+£482.81
6
+£1,703.92
+£74,348.82
+£49,413.68
Monitoring
Year 1
Year 2
6 total
Aflibercept
7 total (no
additional
visits)
Cost saving
Cost saving
Cost saving
Cost saving
12 total
+£637.92
(visits)
+£398.70
(visits)
+£35,245.08
(visits)
+£11,562.30 (visits)
+£586.30
(OCT)
+£51,828.92
(OCT)
Ranibizumab
(8 separate
visits)
+£938.08
(OCT)
(4 separate
visits)
12 total
(9 separate
visits)
+£17,002.70 (OCT)
Per 100,000 population, 34 wet AMD eyes eligible for treatment based on NICE treatment criteria
Assuming the above assumptions in the first two years per 100,000 in the UK, Bayer Healthcare have estimated that this
leads to a saving with aflibercept of £123,763 based on reduced injections alone, a saving of £46,807 aflibercept based
on reduced monitoring visits alone and a saving of £68,832 with aflibercept based on reduced OCT. These savings with
aflibercept total approximately £239,400 per 100,000 population over two years.