The Cardiovascular Safety of Lucentis® compared to Macugen®
We’re getting more data to assess the safety of these two drugs when injected intraocularly to treat AMD. The VISION trial group released both one and two-year safety data on pegaptanib (Macugen®). At one-year, serious thromboembolic events occurred in 4% of patient in both the sham and the Macugen groups. After two years, the risk of all thromboemblic events was 5% in the Macugen group and 10% in the sham group, although there were only 51 patients in the sham group. The serious thromboembolic events at two years were 3% in the Macugen group and 8% in the sham group. (1) Miller at ARVO, presented the two-year study results for the MARINA trial which used intravitreal ranibizumab (Lucentis®). At two-years, the risk of cerebral vascular events or heart attacks was 3% in the sham group; 4.6% in the 0.3mg Lucentis group; and 4.2% in the 0.5mg Lucentis group. (2) To me these results mean: About 5% of patients with wet AMD are going to have a stroke or a heart attack over two years without any treatment for wet AMD.
The risk in patients who have had intravitreal Macugen nor Lucentis is about the same as the untreated groups.
That therefore probably neither drug increases the risk of a stroke or heart attacks.
That both drugs have about the same risk or more accurately, the same non-risk.
References
D'Amico DJ; VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group; Patel M, Adamis AP, Cunningham ET Jr, Guyer DR, Katz B. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006 Jun;113(6):992-1001. ( Ophthalmology. 2006 Jun;113(6):1001.e1-6. Epub 2006 Apr 27.)
Miller JW, et al. Randomized, controlled phase III study of ranibizumab (Lucentis™) for minimally classic or occult neovascular age-related macular degeneration: two-year safety results of the MARINA study. [ARVO 2006 poster 3539]. Available from http://tinyurl.com/gbqsp, program number 3539. Accessed June 15, 2006.
PIER and Torpedoes for Lucentis
The PIER study evaluated whether Lucentis could be injected into the eye less often than once a month and still be effective for the treatment of wet AMD. Treated patients received three monthly injections and then injections every three months at month five, eight, and eleven. After twelve months of follow-up, treated patients had the same vision as they did at baseline whereas the sham treatment group had lost 16.3 letters.(1)
These are good results but not as good as in the MARINA trial in which patients received Lucentis every month. The treated patients in the MARINA trial had a net gain of about one to one and a half lines of vision. Therefore it appears that patients would forfeit this small but significant gain in vision if they followed the dosing schedule used in the PIER study.
Lucentis will probably be approved June 30th and patients do best if they’re injected once a month.(2) So why is it not smooth sailing for Genentech? Retinal experts who are the ones who treat most of the AMD are still a little miffed about the high cost of Visudyne and Macugen. The high cost of those treatments is not Genentech’s fault of course, since Visudyne is sold by Novartis and Macugen by Eyetech. But the retinal doctors are waiting with bated breath to see the price Genentech charges for Lucentis.
Last week was our Iowa Eye Annual Meeting and I asked maybe ten retinal experts from around the country what he or she thought would be the price of a dose of Lucentis. The estimates varied from $400 to $3000 dollars per 0.5mg dose. If Genentech charges a $1000 or less per dose, retinal experts will probably be very happy to use Lucentis and they will use a lot of it. If the cost goes higher, the retinal docs may cause trouble. They may try to use the cheaper Avastin. They may try to give one or two doses of Lucentis followed by a Visudyne treatment using a low total light dose.
In the FOCUS study, patients who were treated with Visudyne plus Lucentis did not do quite as well as those treated in other trials with monthly Lucentis. Many retinal experts now believe however, that Visudyne or PDT can close new blood vessels in AMD even when only a half or even a quarter of the recommend light dose is used.(3,4) The lower light dose will cause fewer side-effects and may have about the same result as monthly Lucentis.
Genentech has tested Lucentis thoroughly, has behaved admirably, and deserves to make a nice profit. The question for them will be whether they want to get all their money back quickly while dodging the torpedoes or will they be content to charge less and have smooth sailing?
References
David Saperstein, MD, University of Washington- Personal Communication
David M. Brown, MD, Houston, Texas – Personal Communication
The Safety of Avastin, Lucentis, Macugen
There has been concern about the safety of VEGF inhibitors because all three get into the systemic circulation after intraocular injection albeit in very tiny amounts. In addition, the first year MARINA results showed a slightly increased rate of cardiovascular events in the Lucentis groups compared to the sham group. Recent reports however have decreased our concerns: Joan Miller presented the two-year results of the MARINA Trial at ARVO. There was no difference in mortality among the sham group (6 deaths), the 0.3mg Lucentis dose group (5 deaths), and the 0.5mg Lucentis dose group (6 deaths). There was also no significant difference among the three groups in hypertension, arterial thromboembolic events, or other cardiovascular events. Fung et al. reported a survey of vitreoretinal experts that included 3,034 patients who had received a total of 3,810 injections of Avastin. The survey showed that only two patients (0.05%) had strokes and that only one patient (0.03%) died. These rates are very low and probably no different than would be found normally in that age-group of patients. A survey can be criticized however because doctors may not want to report that one of his or her patients had a problem. Some patients don’t come back either and unless the doctor called every patient who had Avastin, he or she might be unaware of a problem. Dave Brown (personal communication) estimates that he and his colleagues have given 1700 doses of Lucentis and haven’t seen systemic complications. In summary, injections of these agents into the eye probably don’t cause an increased risk of cardiovascular or any other systemic problems but it is still possible that they could cause a very miniscule increased risk. This tiny increased risk would not dissuade me from having an injection that would save or even increase my vision. References:Patel M, et al. Population pharmacokinetics/pharmacodynamics (PK/PD) of pegaptanib sodium (Macugen®) in patients with age-related macular degeneration (AMD). [ARVO 2006 poster 2623/B782]. Available from http://tinyurl.com/gbqsp, program number 2623. Accessed June 15, 2006.
Miller JW, et al. Randomized, controlled phase III study of ranibizumab (Lucentis™) for minimally classic or occult neovascular age-related macular degeneration: two-year safety results of the MARINA study. [ARVO 2006 poster 3539]. Available from http://tinyurl.com/gbqsp, program number 3539. Accessed June 15, 2006.
Brown DM. Conference report: Highlights if the Association for Research in Vision and Ophthalmology 2006 Annnual Meeting. AMD Special Report CME Newsletter, volume 4. Available from http://www.medscape.com/viewprogram/5459. Accessed June 15, 2006.
Fung AE, et al. Intravitreal Avastin® safety survey: results from the world wide web. [ARVO 2006 poster 5251/B666]. Available from http://tinyurl.com/gbqsp, program number 5251. Accessed June 15, 2006.
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OUCH! 3-1-2007
Vision Loss Simulators
It is difficult for the normal sighted person to understand the vision loss suffered by someone with AMD. Following is an excellent way to simulate this vision loss written by Dr. Mark Wilkinson, the co-author of our book, Protect Your Sight.
Vision Loss Simulators
by Mark Wilkinson, O.D. I am often asked to describe how a person with macular degeneration sees. Many pictures are available that attempt to demonstrate loss of vision from macular degeneration. These pictures often show a central blind spot (scotoma) with the surrounding area appearing fairly clear. These pictures imply that if you just move the blind spot out of the way, everything will be clear. Unfortunately, this is not the case. Our peripheral vision is designed to provide us with vision under low light conditions. Our peripheral vision is not capable of the same level of detail vision as our macula is without the use of optical or electronic magnification. In addition, with vision loss from macular degeneration, there is commonly a decrease in contrast sensitivity. The reduced contrast sensitivity makes it more difficult to see details when looking at faces or reading a newspaper. A simple way to simulate the vision loss in AMD can be accomplished by looking through Ziploc® bags (I have not tested other brands of these bags, but they are likely about the same). To simulate early vision loss, look through a Ziploc® sandwich bag. The sandwich bag will decrease vision by a factor of 2. Thus a person with normal 20/20 vision would see 20/40 though the bag. Folding the bag over on top of itself or looking through 2 bags, decreases the vision about 4x, like going from 20/20 to 20/80 vision. Looking through a 2 gallon Ziploc® storage bag decreases vision just over ten times, like going from 20/20 to a little poorer than 20/200 vision. If you fold this big bag over and look through it, your vision will be decreased 20 times or from 20/20 to 20/400. These simulations will work equally well for distance and near visual tasks and are more realistic than other simulations. The method also simulates the vision loss from a cataract or a scar in the cornea.
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