Friday, September 26, 2008

CATT Revisited

I’ve written before about the Comparisons of AMD Treatments Trials (CATT). Recruitment of wet AMD patients is well underway into a study that compares four groups:

1. Monthly Lucentis® injections.

2. Monthly Avastin® injections.

3. One Lucentis injection followed by monthly visits and additional injections only as needed.

4. One Avastin injection followed by monthly visits and additional injections only as needed.

Genentech,which makes both drugs, has stated that Lucentis is the proven drug for AMD and should be used instead of Avastin. Retinal surgeons however, have generally found that both drugs are effective. Retinal surgeons are switching from Lucentis to Avastin. I think around 80% of the retinal experts in this country are now using Avastin in lieu of Lucentis. They feel that Avastin works just as well, is cheaper, and lasts longer in the eye resulting in less frequent injections.

Genentech was not supportive of the Lucentis versus Avastin trial especially since they were selling billions of dollars worth of Lucentis. But now, with the sales of Lucentis flat or even falling, the results of this trial could benefit them. I personally believe that there will not be much of a difference between the two drugs. But if the trial shows that the visual results are better with Lucentis, retinal surgeons will be hard pressed to recommend Avastin to their patients.

But the biggest boon to sales may be in the comparison of groups 3&4 above to groups 1&2. Most retinal surgeons now follow a protocol similar to groups 3&4. If the retina is dry, they may decide not to reinject. Many doctors may still reinject but then increase the number of weeks until the next visit. When you think about it, we’re often waiting for a relapse of swelling before doing another injection. There is a greater likelihood that groups 3&4 won’t do as well as group 1&2 than there is a chance that one drug is better than the other. If this is the case, Genentech still wins, because now injections will be given more often, perhaps even once a month. More injections equal more drug sold.

We have complained about the high price of Lucentis but both of these drugs have saved vision in countless patients with wet AMD.

See also blogs:
Avastin vs. Lucentis. March 26, 2008
Academy and Retinal Specialists Meet with Genentech. October 30, 2007
Clinical Trials for Wet AMD. August 27, 2007

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Monday, September 22, 2008

A Very Big Clue to Understanding Dry AMD

Dry AMD with atrophy is still a big cause of vision loss. Vitamin and zinc supplements reduce the rate of vision loss in AMD mainly by decreasing the risk of developing new blood vessels or wet AMD. Non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, or naproxen may decrease the rate of progression to atrophy by decreasing inflammation but they aren’t a cure all.

There was a very interesting article which is scheduled to be published in the October 2, 2008 issue of the New England Journal of Medicine showing an association of variants in the toll-like receptor 3 gene with decreasing the risk of geographic atrophy in people with AMD. This receptor encodes for a viral sensor that is associated with innate immunity-meaning fighting off viral infections.

The scientists put two genetically different toll-like receptors in mice and then injected double stranded RNA into the vitreous; this is analogous to getting a virus. The variant of the receptor that protected against atrophy in people with AMD protected against cell death of the pigment epithelium in mice compared to the normal variant.

How about in layperson’s terms? The idea is that a virus that contains double stranded RNA infects the retinal pigment epithelium. The toll-like receptors are activated to fight the virus. One genetic variant of the receptor perhaps causes more inflammation causing the death of the retinal pigment epithelial cell compared to the other variant. Once again, too much inflammation might be bad.

So how to you decrease atrophy in dry AMD? You can have the genetic variant of toll-like receptor that protects against atrophy. If you don’t have this variant in your genes, perhaps in the future you’ll be able to get the good variant transplanted into your retina. The hooker with this is that usually genes are transplanted via viruses and viruses might be bad especially if you have AMD. Probably a more realistic route would be to decrease the inflammation in the outer retina. We don’t know how to selectively decrease the inflammation started by the toll-like receptor. For now, I would still take 325 mg of aspirin, 200mg of ibuprofen, or 275mg of Naproxen a day.

We need much more information but this recent study is a very impressive start into understanding a complex disease.

References:

1. Yang, Z, Straaton, C, Francis, PJ, et al. Toll-like Receptor 3 and Geographic Atrophy in Age-Related Macular Degeneration. N Engl J Med. 2008;359(14):1456-1463

(reference updated 10-2-2008)

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Wednesday, July 30, 2008

Bye….Bye…Beta-carotene. Say hello to Lutein/zeaxanthine

It’s been a bad year for beta-carotene.

Beta-carotene was part of the AREDS I supplementation along with vitamins C, E, zinc, and copper. This combination reduced the progression to severe AMD by about 25% over five years. The dose of beta-carotene used in AREDS I was a whopping 15mg, about 28,000 IU per day and about six times the daily recommended value. The Physicians’ Health study however showed no difference in AMD between those taking a supplement of 50mg of beta-carotene every other day compared to those who did not.(1) This result was one of the reasons that the AREDS II trial includes a group that is randomized to no beta-carotene (see January 22, 2007 blog on AREDS II).

Now there is concern that extra beta-carotene might actually make AMD worse. Beta-carotene becomes vitamin A, or retinol, which is necessary for sight. In the outer segments of the cones and rods, all trans-retinol is converted to cis-retinol when exposed to light and this starts the electro-chemical process of seeing. If there is no vitamin A, there is no sight. The problem is that the eye doesn’t perfectly recycle the retinol. There are a variety of breakdown products, called retinoids, which accumulate in macular degeneration. One of the breakdown products, called A2E is considered to be especially toxic. There is one study that is testing a drug that binds to the same transport proteins that are used by retinol to get into the eye (see November 19, 2007 blog, Age Related Macular Degeneration: Treatments for Dry AMD). The idea is to prevent an excess of retinol in the eye which will limit the production of A2E and potentially other harmful retinoids. It is hoped that this will reduce the progression of AMD especially the dry or atrophic form. This is analogous to starving the eye a bit from retinol and is the exact opposite idea of supplementing with high doses of beta-carotene!

A recent study from Australia showed that dietary lutein and zeaxanthin reduced the risk of the development of AMD long-term.(2) The same study showed that a high intake of beta-carotene was associated with an increased risk of AMD.

A study from Italy in the same journal showed that short term supplementation with vitamin C, E, copper, zinc, lutein, zeaxanthin, and astaxanthin increased macular function as measured by a special test called a multifocal electroretinogram.(3) Notice that no beta-carotene was used in their patients.

I would recommend an AREDS supplement with lutein especially and also zeaxanthine if you can get it. The doses used in AREDS II are 10 mg lutein and 2mg zexanthine. Don’t take beta-carotene if you’re a smoker since it increases the risk of lung cancer. I would also limit or eliminate the amount of beta-carotene supplements even if you’re not a smoker.

Just eat your vegetables.

References:

1. Christen WG, Glynn RJ, Ajani UA, et al. Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol 2001; 119: 1143-9.

2. Tan, JSL, Wang, JJ, “Dietarty Antioxidants and the Long-term Incidence of Age-Related Macular Degeneration.” Ophthalmology 2008;115-334-341.

3. Parisi, V., Tedeschi, M, “Carotenoids and Antioxidants in Age-Related Maculopathy Italian Study.” Ophthalmology 2008;115:324-333.

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