Macular Degeneration - Update on clinical trial results and new treatments

Update on Clinical Trial Results and New Treatments For Macular Degeneration

Anil AroraCentral Coast Optometrist Conference2nd March 2014

Studies

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)

AREDS STUDY

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

AREDS STUDY (contd.)

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 AMDCategory 3: intermediate AMDCategory 4: advanced AMD in one eye

Category 2, 3 and 4 randomized to receive: 1. Placebo2. Antioxidants alone3. Zinc alone4. 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

AREDS STUDY (contd.)

ResultsFor category 2, only 13% of patients progressed to advanced

AMD.

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.

ConclusionIt was recommended that patients with intermediate or

advanced AMD should consider taking antioxidant vitamins and zinc

AREDS

Without treatment, patients with intermediate AMD had an 18% chance of progressing to advanced AMD in one or both eyes over 5 years.

Without treatment, patients with advanced AMD 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.

Intermediate stage ARMD 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

Original AREDS formulation 500 mg vitamin C 400 IU vitamin E 15 milligrams of beta-carotene (or

25,000 international units of vitamin A) 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

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

AREDS 2 findings

The key findings of the study were as follows: The addition of DHA/EPA (fish oil) to the original AREDS 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 stage AMD.

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.

AREDS 2 recommendations The AREDS 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)

A quick word about saffron

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).

CATT and IVAN studies

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-Related Choroidal

Neovascularization (IVAN) study

Bevacizumab (Avastin)

Bevacizumab is a 149-kD humanized monoclonal antibody that inhibits VEGF-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.

Ranibizumab (Lucentis)

This 48-kD monoclonal antibody fragment (also referred to as an “Fab fragment”) inhibits VEGF 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 Drug Administration in June 2006 for the treatment of neovascular AMD.

CATT Trial:

History 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.

CATT Trial:

Two-Year Primary Outcomes 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.

CATT Trial:

Two-Year Safety Data

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%).

CATT Trial:


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

CATT Trial:


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.

CATT Trial:

Two-Year Cost Analysis

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

CATT Trial:

Summary of Two-Year Results

IVAN Trial:

History and Subjects

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.

IVAN Trial:

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

Most expensive substances in the world by weight

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.

Highest Government Cost Drug by PBS Item, year ending June 2012

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 3,801,902 244,513,668 294,966,16377.58


4 9043 Rosuvastatin Tablet 10mg 3,109,370 137,757,812 187,826,48360.41


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 100 257,521 105,993,516 109,441,150424.98

9 9044 Rosuvastatin Tablet 20mg 1,552,001 104,050,806 129,174,65683.23

10 8601 Esomeprazole Tablet 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

Also of concern – higher rate of late geographic atrophy with Lucentis

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)

WATCH THIS SPACE!!

VA = Counting fingers

After 15 Lucentis injections and $30,000 VA = counting fingers

MD foundation statement on CATT results

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”.

Macular degeneration foundation – major sponsors

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.

http://www.novartis.com.au/

http://www.blackmores.com.au/

http://www.bayer.com.au/scripts/pages/en/index.php

Influencing the thoughts of our thought leaders? Functions organised by Novartis for leading medical retina specialists

Well worth a read – Google: Australia’s billion dollar blind spot

Australia’s Billion-Dollar Blind Spot

By Mike SeccombeMay 10, 2013 The 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.

http://www.theglobalmail.org/reporters/mike-seccombe/1/

http://www.theglobalmail.org/reporters/mike-seccombe/1/

The dilemma

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?

Statement from retinal physicians

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

Conclusion from Daniel Martin – Chair of the CATT study group

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.

You don’t have to be a superhero to see what’s the most cost-effective option

MCQ’s

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

MCQ’s

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 reducing AMD progressionc) beta carotene was associated with an increased risk of lung cancer, especially in current or past smokersd) beta carotene reduced the dietary absorption of lutein and xeaxanthin

MCQ’s

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

Answers

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

Macular Degeneration - Update on clinical trial results and new treatments

Education

risk of amd

intermediate amd category

early amd category

case of advanced amd

progression of dry amd

zinc oxide copper

risk of progression

eye category