by Dan Roberts
Updated February 2007
(Editor’s note: This article is retained for archival purposes. More recent developments will be found elsewhere in the Low Vision Resources Library.)
Off-label use of intravitreal Avastin (bevacizumab) has become a widespread treatment for wet AMD. This is a concern for some doctors and for Genentech Pharmaceuticals (developers of Avastin for cancer treatment and Lucentis for retinal treatment), as no major scientific proof of safety or efficacy has yet been demonstrated for the drug’s use in retinal therapy. At the annual meeting of the American Academy of Ophthalmologist on October 14, 2005, Genentech presented several areas of concern about the drug’s potentially adverse effects when used intravitreally for wet AMD:
1) Avastin contains no preservatives, so there could be problems in keeping it sterile when it is split up by doctors into the small quantities required for retinal treatment.
2) No pre-clinical trial toxicity data exists for use of Avastin in retinal therapy.
3) The half-life of Avastin is different than Lucentis, in that it clears from the system 100 times slower. This is important for cancer use, but remaining in the retina for that length of time could be harmful.
4) Lucentis binds more strongly to the VEGF protein than Avastin. It is this binding that blocks the protein from developing blood vessel growth into the retina (neovascularization).
5) Avastin contains full-length antibodies, which can cause inflammation. The antibody fragments in Lucentis are 1/3 the size of Avastin antibodies, so they are capable of better penetration through the retinal layers.
6) Manufacturing standards differ for cancer and ophthalmic drugs. Particulate matter must be very low in drugs used in the eye, and Avastin is not manufactured with that in mind.
Phil Rosenfeld, M.D. (who is leading the study of Avastin for retinal treatment at the Bascom Palmer Eye Institute in Miami) told MD Support that the issue of purity is not a problem in his work. His lab takes every precaution to have the drug safely divided into the desired dosages for injection, and they have had no safety issues so far. The other concerns, he said, are theoretical, not having presented themselves as problems in actual practice.
In order to develop Avastin into a safe and effective drug for wet AMD, Genentech says that they would have to start at the pre-clinical trial stage. Considering the involvement of time (5-7 years), they maintain that such an effort would be fruitless when Lucentis is already in place and proving its value.
Regarding the large cost difference between the two drugs, the company holds that it should not be a serious concern, as treatment is fully-accepted by insurance and Medicare. Genentech also has in place their “Access to Care” foundation to provide financial assistance to patients if needed.
Genentech strongly states that their decision to not pursue Avastin as a treatment option for retinal degeneration is not financially-based. The cost of such research would be high, they say, but to invest so much time and money trying to prove the dubious theory that Avastin is as good as Lucentis would be counterproductive when there are more important areas that need attention.
Despite concerns about Avastin, small studies and clinical observations have recently shown that intravitreal treatment with Avastin is showing no systemic adverse events and that the drug is showing success in inhibiting neovascularization and improving visual acuity. The general conclusion is that re-treatment is needed at 2-3 month intervals. Three of these studies, presented as poster sessions at the 2006 meeting of the AAO, are:
“Intravitreal bevacizumab (Avastin) in the treatment of neovascular age-related macular degeneration” (Avery, RL, et al, Poster #673).
“Intravitreal bevacizumab (Avastin) for recurrent choroidal neovascularization” (Frederico Graue-Wiechers, et al, Poster #722).
“Safety and effectiveness of intravitreal bevacizumab for subfoveal choroidal neovascularization in pathologic myopia” (Hernandez-Rojas, ML, et al, Poster #673).
In line with the latter study, Elias Reichel, M.D. reported to Hawaiian Eye/Retina 2007 that Avastin has shown good results in a small retrospective case series for treatment of neovascularization from myopic degeneration. 15 eyes studied showed a mean improvement in acuity of 3 lines. Baseline visual acuity was 20/20 to 20/40 in one eye, 20/50 to 20/100 in eight eyes and 20/200 or worse in six eyes. At the last follow-up exam, six eyes were 20/20 to 20/40, seven eyes were 20/50 to 20/100, and only two eyes were 20/200 or worse. Baseline central foveal thickness was 324 µm (micrometers) and, at 10 months, central foveal thickness was 229 µm, for an average reduction of 93 µm.
by Dan Roberts