Macular Degeneration - Update on clinical trial results and new treatments

Anil Arora
Central Coast Optometrist Conference
2nd March 2014

 The studies that I specifically will discuss are:
 AREDS (Age-Related Eye Disease Study)
 AREDS 2
 CATT (Comparison of AMD Treatments Trial)
 IVAN (Inhibition of VEGF in Age-Related
Choroidal Neovascularization)

Aim
To evaluate the effect of anti-oxidant vitamins and
zinc on the progression of dry AMD. The study was
initiated by National Institutes of Health.
No. of centres
11
No. of people
4767 participants aged 55-80 years

Patients divided into 4 categories:
Category 1: little or no AMD -> randomized to antioxidants or placebo to determine any
effect on lens changes
Category 2: early AMD
Category 3: intermediate AMD
Category 4: advanced AMD in one eye
Category 2, 3 and 4 randomized to receive:
1. Placebo
2. Antioxidants alone
3. Zinc alone
4. Antioxidants plus zinc (Vit. C: 500 mg,Vit. E: 400 IU, Betacarotene: 15 mg, Zn oxide:
80 mg, Copper: 2mg)
Category 2, 3, 4 were followed for visual loss for the development of advanced AMD
Patients followed up: 6.3 years

Results
For category 2, only 13% of patients progressed to advancedAMD.
For categories 3 and 4 (who are at greater risk for developing advanced
AMD), it was found that the combination of zinc and antioxidants were
most effective in reducing the progression to advanced AMD.
Conclusion
It was recommended that patients with intermediate or advancedAMD
should consider taking antioxidant vitamins and zinc

 Without treatment, patients with intermediate AMD had an 18%
chance of progressing to advancedAMD in one or both eyes over 5
years.
 Without treatment, patients with advancedAMD in one eye had a
43% chance of progressing to advanced AMD in the other eye.
 With treatment, high risk patients decreased their risk of
progressing to advanced AMD by 25% (in the case of advanced
AMD in one eye, this decreased risk refers to the other eye).
 With treatment, risk of moderate or severe vision loss was
decreased by 19% over 5 years.
 Treatment did not slow progression from early AMD to
intermediate AMD.
 There was no evidence that vision loss or disease progression
was reversed in any treatment group.

 Eyes with numerous
(>20 indistinct or 50
distinct) medium-sized
drusen or one or more
large drusen (arbitrarily
defined as >125
µm, which is
approximately the size
of a retinal vein at the
optic disc) or non-
central geographic
atrophy

 500 mg vitaminC
 400 IU vitamin E
 15 milligrams of beta-carotene (or 25,000
international units of vitaminA)
 80 mg of zinc, in the form of zinc oxide
 2 mg of copper as cupric oxide, added to
prevent copper deficiency anaemia, a
condition associated with high levels of zinc
intake

 AREDS 2, a five-year study designed to test
whether the originalAREDS formulation
would be improved by:
 adding omega-3 fatty acids
 adding lutein and zeaxanthin
 removing beta-carotene
 or reducing zinc.

 The key findings of the study were as follows:
 The addition of DHA/EPA (fish oil) to the originalAREDS formulation did
not provide any further benefit. NOTE: Several other large population
studies have consistently shown that the consumption of actual fish
significantly reduces the risk of AMD.
 The addition of lutein/zeaxanthin provided a small benefit, which was
significantly greater for people who had the lowest intake of lutein in
their regular diet. In a sub-group analysis, it was also shown that when
beta-carotene was removed from the original formulation, and replaced
with lutein/zeaxanthin, there was an 18% additional reduction in the risk
of progression to late stageAMD.
 A clear recommendation from AREDS2 was for the removal of beta-
carotene from the supplement, as it:
 Did not contribute to efficacy
 Increased the risk of lung cancer, especially in people who smoke or previously
smoked
 Led to a reduced absorption of lutein/zeaxanthin.

 TheAREDS study group recommended the continued
use of the original AREDS formulation, but with beta-
carotene removed, to be replaced by
lutein/zeaxanthin.The use of a fish oil supplement
could not be recommended based on these results.
 The recommended daily dose was therefore:
 Zinc (80 mg as zinc oxide)
Copper (2 mg as copper oxide)
Vitamin E (400 IU)
Vitamin C (500 mg)
Lutein (10 mg)
Zeaxanthin (2 mg)

 Gaining some interest as a possible
treatment for ARMD
 Powerful antioxidant
 Studies showed that mice pre-fed with
saffron had lower rates of
photoreceptor death than controls
when exposed to intense light
 Improved photoreceptor electrical
signals in patients given saffron
 Lots of anecdotal reports and
testimonials
 No “robust evidence”
 Cheap (about 50cents for a once-daily
20mg capsule –about$25 per gram)and
no significant side effects
 ?worth recommending on the “at least
it won’t do you any harm “ principle?
●The stigma from saffron is a
spice, harvested from the Crocus sativus
flower, a member of the iris family.
● It takes the stigmas from 85,000 flowers to
get just 1 kilogram of raw saffron.
●After drying, this yields only 200 grams of
saffron powder! (That’s why it’s the world’s
most expensive spice).

 Questions about the efficacy and safety of
Avastin and Lucentis in relation to one another
have been present for several years.
 To compare the efficacy and safety of
bevacizumab(Avastin) and ranibizumab
(Lucentis) treatment, two head-to-
head, multicenter, randomized clinical trials
were initiated:
 The Comparison of AMD Treatments Trial (CATT)
 The Inhibition of VEGF in Age-RelatedChoroidal
Neovascularization (IVAN) study

 Bevacizumab is a 149-kD humanized
monoclonal antibody that inhibitsVEGF-A, a
signal protein that stimulates angiogenesis and
vasculogenesis in AMD.
 It is intended solely for use in the management
of various cancers.
 Bevacizumab has been shown to decrease
retinal thickness and increase visual acuity in
patients with exudative AMD.
 It is frequently used off-label for the treatment
of neovascular AMD.

 This 48-kD monoclonal antibody fragment (also
referred to as an “Fab fragment”) inhibitsVEGF
and is specifically formulated for intraocular use.
 In several randomized clinical trials, intraocular
administration of ranibizumab dramatically
improved the visual acuity of patients with
exudative AMD with minimal side effects.
 Ranibizumab was approved by the US Food and
DrugAdministration in June 2006 for the
treatment of neovascular AMD.

 CATT, a
multicenter, prospective, noninferiority, clinical trial
funded by the National Eye Institute, evaluated the
safety and efficacy of ranibizumab or bevacizumab
in the treatment of exudative AMD.
 The trial began in February 2008.
 It initially enrolled 1,208 patients with neovascular
AMD at 44 clinical centers within the United States.
 Recruitment occurred from February 2008 through
December 2009.
 1-year results published in May 2011.

 No statistical difference in visual acuity between
ranibizumab and bevacizumab therapy was found
after 2 years.
 The mean increase in visual acuity from baseline was:
 8.8 letters in the monthly ranibizumab group
 7.8 letters in the monthly bevacizumab group
 6.7 letters in the ranibizumab as-needed group
 5.0 letters in the bevacizumab as-needed group.
 In most cases, greater improvement in visual acuity
occurred during the first year than it did during the
second year of the study.

 The rates of death, ATEs, and venous thrombotic
events were similar among the four treatment
groups.
 There was a trend toward a higher risk of venous
thrombotic events among patients using
bevacizumab.
 The percentage of patients with one or more
serious systemic adverse events was higher in
the bevacizumab group (39.9%) than in the
ranibizumab group (31.7%).

Note that the as-needed groups had a higher rate of adverse events than the monthly
injection groups for both Avastin and Lucentis.

 As in the first year of the trial, the rate of GI
disorders (GI bleeding, hernias, diverticular
disease)in patients given bevacizumab was higher
than among those given ranibizumab.
 There was no difference in ocular-related adverse
events, such as endophthalmitis, in either drug
group. 11 cases of endophthalmitis in about 19,000
injections (incidence = 0.06%)
 However, 10 of the 11 cases of endophthalmitis
occurred in the groups receiving bevacizumab or
ranibizumab monthly.

Two-year costs varied from $705 in the as-
needed bevacizumab group to $44,800 in the
monthly ranibizumab group.

 IVAN is an ongoing head-to-head comparison of
the efficacy and safety of bevacizumab and
ranibizumab in patients with exudative AMD.
 It is being conducted at 23 clinical centers in the
United Kingdom and is sponsored by the
National Institute for Health Research.
 The investigators had a target of 600 patients
for enrollment, with only one eye per patient
included in the study.
 One year results published in June 2012.

There were no clinically important differences in visual
acuity or any secondary functional outcomes between
ranibizumab and bevacizumab after 1 year.8

 Gold – about $ 1450 per
ounce = ~$55 per gram

 Crystal Meth (Ice)
– about $100 per gram

 Heroin – about $150
per gram

 Cocaine – about $250
per gram

 LSD
- lysergic acid
diethylamine
- “Lucy in the sky
with diamonds”
- About $ 3,000 per gram

 Diamonds – a high
quality diamond can
cost about $50,000 per
gram ($10,000 per
carat, 1 carat =0.2g)

 Lucentis
 $2,000 for 0.5 mg
 $4,000,000 per gram
 - Lucy in the eye can
buy lots of diamonds
 Avastin
 $ ~50 for 3 mg
 $ ~ 15,000 per gram

 Californium 252
 Cost: $ 27 million per gram
 What you do with it:The
Californium isotope actually doesn't
really have any practical uses. It's
only been created once in the
western world since it was
discovered in 1950
 Antimatter
 Cost: $62.5 trillion per gram
 What you do with it: Antimatter
could possibly fuel spaceships to the
planets, and maybe the stars, in the
years to come.

 Rank Item Drug Form Volume Govt Cost $ Total Cost $ Ave Price $
 1 1382 Ranibizumab Solution 145,018 307,816,693 309,202,570 2132.17
 2 8215 Atorvastatin Tablet 40mg 3,801,902 244,513,668 294,966,163 77.58
 4 9043 Rosuvastatin Tablet 10mg 3,109,370 137,757,812 187,826,483 60.41
 6 8626 Tiotropium Capsule 1,695,976 117,857,405 130,360,593 76.86
 7 8358 Clopidogrel Tablet 75mg 2,069,342 113,668,782 131,441,335 63.52
 8 9039 Insulin Glarg Injections 100 257,521 105,993,516 109,441,150 424.98
 9 9044 Rosuvastatin Tablet 20mg 1,552,001 104,050,806 129,174,656 83.23
 10 8601 EsomeprazoleTablet 2,720,273 91,032,703 125,681,659 46.20
Lucentis cost the taxpayer over $300 million in 2011-12 and has cost the taxpayer over $1.5
billion since it was subsidised in 2007

 The proportion of study eyes
with geographic atrophy at
two years among eyes
without apparent geographic
atrophy at
enrollment, ranging from
25.8% in the ranibizumab
monthly group to 12.9% in
the bevacizumab as-needed
group, was greater among
patients treated monthly (P =
.007)
 WATCHTHIS SPACE!!
VA = Counting fingers
After 15 Lucentis injections and
$30,000 VA = counting fingers

 The Chair of the MD Foundation Medical Committee Dr Paul Beaumont stated today
that “the CATT study indicates that ranibizumab (Lucentis) and bevacizumab
(Avastin) produce similar visual acuity outcomes for the treatment of wet Age-related
Macular Degeneration, however bevacizumab may be less effective in reducing
the retinal swelling that occurs with this disease. More research is needed to
determine if this will adversely affect longer term outcomes.” “There are still
unanswered questions regarding the safety of bevacizumab.There were more
serious systemic adverse events in the bevacizumab group including more
hospitalizations over the study period.” “The numbers of deaths, heart attacks and
strokes which followed treatment were low, with similar numbers occurring in each
treatment group. Unfortunately, CATT did not have enough patients to determine
whether there were any meaningful differences in these serious but rare side effects.”
It is imperative that we never compromise safety and this why the registration and
reimbursement of drugs in Australia is evidence-based pertaining to both efficacy
and safety.There are of course, specific circumstances whereby drugs are used off
label and this must always be on a case by case basis in discussion between doctor
and patient. The most appropriate treatment for patients with wet AMD currently
approved by the Therapeutic Goods Administration remains ranibizumab.
CATT study raises more questions than it answers
Foundation CEO Julie Heraghty describes Avastin as being “better than
nothing”.

 Corporate / Organisation Supporters
Novartis has been a supporter of the Foundation since its beginnings
in 2001. Over this time Novartis has generously funded a range of
Foundation projects and activities, most notably in the areas of
awareness, education and research. Novartis also supported the
national advertising campaigns airing from 2008 to 2012.
 Blackmores has also been a supporter of the Foundation since its
beginnings in 2001. Blackmores generously provide the Foundation a
percentage of sales from its range of macular health supplements and
also supports awareness, research and education activities.
 Bayer has been a generous sponsor of the Foundation since 2011
(about the time that Eylea came out). Bayer's funding makes a
valuable contribution to the work of the Foundation and the services it
delivers in the areas of research, education, awareness, representation
and client services.

 Australia’s Billion-Dollar
Blind Spot
 By Mike SeccombeMay 10,
2013The Global Mail
 What if the government
could save hundreds of
millions of dollars by listing a
cheaper drug, shown to be
just as effective as the one
which costs the PBS more
than any other medicine?You
won’t find out so long as the
company that owns both
drugs keeps the bargain-
priced cousin shut out.

 Do ophthalmologists who perform intravitreal injections have a
responsibility that goes beyond treating the patient the patient
sitting in front of them? Is there a responsibility for the healthcare
dollar and the taxpayer?
 Should ophthalmologists give some thought as to what the $300-
$400 million per year savings by not subsidising Lucentis could do
for the health system?
 If CATT, IVAN and other studies show equal effectiveness between
two options and a far greater cost-effectiveness for one of
these, are clinicians being irresponsible in choosing the more
expensive option?
 Despite CATT and IVAN many ophthalmologists have concerns
about using an “off-label” drug.
 Should we at least adopt a user-pays scheme – if a patient or
doctor wants Lucentis the patient pays the $2,000 rather than the
taxpayer?

 With this data, and the minimal differences in
outcomes that it demonstrates, should we not be
turning to the important issues of cost and
effectiveness for our healthcare dollars? I would feel
that the greater moral imperative would be to use a
drug with a greater cost effectiveness and therefore
treat more patients than chase an outcome that for
the vast majority of patients will make no
difference. If we do not drive this agenda ourselves it
will be the healthcare bureaucrats who will drive the
agenda and in fact reduce our treatment choices

 The good news is that now we can use both
drugs to treat our wet AMD patients with more
confidence and with a higher level of evidence.
Lucentis remains the standard of care but
Avastin will no longer be only "the cheaper drug"
when a patient cannot afford Lucentis. The real
incidence of geographic atrophy with monthly
Lucentis should be more investigated. If
confirmed, it would raise more concerns
among ophthalmologists than some systemic
side effects.

Here's the bottom line. We (the global we of society) cannot afford Lucentis. I
know that's a very harsh crude thing to say, but it's true.The incidence of AMD is
rising.Any anti-VEGF treatment is just that...a treatment. It's simple math. We
will cripple Medicare with Lucentis as the mainstay of treatment for wet
AMD. It's not a matter of if; it's a matter of when.
Money is what this boils down to at the end of the day. There are only so many
dollars to go around.Yes, we want to give our patients the best but you
cannot justify bankrupting Medicare to preserve 3 lines of vision in the vast
majority of patients, especially when a viable alternative is available. I don't
think anyone would argue that Avastin is a viable alternative. Is it exactly the
same? Probably not. Does either drug work perfectly for any given population?
Of course not. Can you justify starting with Lucentis when you have a patient
with no suggestion of significant co-morbidities for AMD? I say no.
Am I saying that Lucentis should be done away with? No, that would be silly.Am
I out to destroy Lucentis? No, I actually think it's an amazing drug It definitely has
a place.The CATT trial has shown it just shouldn't be the go-to, out-of-the-
gate choice in the majority of cases

 Among all organ systems, the greatest imbalance was in gastrointestinal
disorders.While the number of events is small, this has been an area of
concern in previous studies of systemic bevacizumab. When all known
VEGF-related SAE’s are excluded, most of the imbalance
remains, leaving us uncertain whether this difference was due to
chance, imbalances at baseline not captured in multivariate
modeling, or truly higher risk. Results from ongoing randomized clinical
trials worldwide may provide additional, independent information on the
risk of treatment with bevacizumab relative to ranibizumab.
 In 2010, ranibizumab accounted for nearly 10% of the entire Medicare
part B drug budget, its single largest expenditure.As treatment of
patients continues indefinitely, the cumulative financial burden to third
party payors and patients will only increase. The choice of drug and
dosing regimen for patients must balance the comparable effects on
vision, the possibility of true differences in adverse events, and the
40-fold difference in cost per dose between ranibizumab and
bevacizumab.

 Q1)The AREDS study suggested that dietary
supplementation with antioxidants and zinc:
a) was beneficial to anyone who had macular drusen
b) could reverse the retinal changes seen in macular
degeneration
c) reduced the risk of progression of intermediate stage
macular degeneration to advanced stageAMD
d) should be given to all family members of patients
with advanced macular degeneration

 Q2)The AREDS 2 study suggested all of the following
except:
a) lutein and xeaxanthin may confer a small additional
effect over the original AREDS formulation, especially
in those with limited dietary intake of these
b) omega-3 fatty acids had a protective effect on
reducingAMD progression
c) beta carotene was associated with an increased risk
of lung cancer, especially in current or past smokers
d) beta carotene reduced the dietary absorption of
lutein and xeaxanthin

 Q3)The CATT and IVAN studies comparingAvastin with
Lucentis showed that:
a) Lucentis results in significantly improved visual
acuity results over Avastin
b) Regular monthly injections with either of these
agents was associated with greater systemic serious
adverse events than as-needed (PRN) injections
c) Avastin results in a greater incidence of late
geographic atrophy than Lucentis
d) Lucentis treatment is far more expensive and far less
cost-effective thanAvastin


Correct answers: Q1 - c, Q2 - b, Q3 - d

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