Macular Degeneration - Update on clinical trial results and new treatments

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Information about Macular Degeneration - Update on clinical trial results and new treatments
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Published on March 20, 2014

Author: presmedaustralia

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Update on Clinical Trial Results and New Treatments For Macular Degeneration

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  3 8214 Atorvastatin Tablet 20mg 3,388,115 148,152,869 193,145,990 57.01  4 9043 Rosuvastatin Tablet 10mg 3,109,370 137,757,812 187,826,483 60.41  5 8521 Atorvastatin Tablet 80mg 1,403,935 132,911,532 151,628,067 108.00  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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