Avastin/Lucentis Update 10: A Review of the Current Status of These Drugs for Treating AMD
This report is reprinted (with permission of the publisher) from the supplement AMD 2006: Building Hope, Improving Vision, published with the December 2006 issue of Review of Ophthalmology.
Treating AMD with Lucentis and Avastin
While these drugs have revolutionized the treatment of AMD, choosing between them remains a challenge.
Philip J. Rosenfeld, MD, PhD Miami
Both Lucentis (ranibizumab, Genentech.) and Avastin (bevacizumab, Genentech) have successfully been used to treat neovascular age-related macular degeneration. While the Avastin experience has been mainly anecdotal and published as retrospective reviews along with small, short-term prospective studies, the Lucentis experience is supported by extensive clinical trial data. Additionally, Lucentis is approved by the Food and Drug Administration for the treatment of neovascular AMD, while Avastin is used off-label for this indication. On the other hand, Avastin is affordable, while Lucentis’ high price may be out of reach for some patients in the United States and for many more globally. Both drugs have advantages that need to be considered when choosing which one to offer patients.
Early Development
Avastin and Lucentis are derived from the same protein. Researchers at Genentech developed a mouse antibody against vascular endothelial growth factor (VEGF). In the 1990s, they made the decision to go in two different directions with the molecule: to humanize the entire mouse molecule for the systemic therapy of cancer and to humanize and affinity mature one of the binding portions of the molecule, which was one third the size of the whole molecule.
They believed that a smaller molecule would be needed to be effective after being injected into the eye. In theory, a smaller molecule would have better penetration and would cause less inflammation in the eye. Additionally, they were concerned about systemic side effects, and they believed that a smaller molecule would be cleared from the systemic circulation faster. In summary, a smaller molecule would have good opportunity for local effectiveness without any risks of systemic toxicity.
There was parallel development of the two molecules, and Avastin was approved for the treatment of colorectal cancer in 2004, and Lucentis was approved for neovascular AMD in 2006.
Avastin
After Lucentis showed promise for the treatment of AMD and systemic Avastin showed promise for the treatment of neovascular AMD, intravitreal Avastin was used as salvage therapy in patients losing vision despite receiving FDA-approved therapies. While no large clinical studies evaluating Avastin for the treatment of AMD have been conducted, the first prospective study using intravitreal bevacizumab for the treatment of neovascular AMD was recently published. (1) This study was conducted in Lebanon by Ziad Bashshur, MD, and colleagues, who administered an intravitreal dose of 2.5 mg in 17 eyes at monthly intervals for the first three injections. They reported their outcomes at 12 weeks, which was four weeks after the last injection. At 12 weeks, mean and median visual acuity had improved, and there was a marked decrease in the 1-mm central retinal thickness measurement obtained using optical coherence tomography. They researchers observed no ocular inflammation or systemic adverse events.
While these results are promising, this study has several limitations. First, the study included only a small number of patients, and they were followed for only 12 weeks. Additionally, only one dosage was studied and questions persist regarding the optimal dose and dosing interval of Avastin, as well as its safety.
The off-label use of Avastin for the treatment of AMD continues to be controversial, with many practitioners questioning the wisdom of injecting Avastin without large, prospective studies to verify its safety. However, many in the vitreoretinal community perceive Avastin to be safe and its efficacy to be equivalent to Lucentis in most patients. But, the overriding feature of Avastin that continues to fuel its widespread use is its low cost.
Lucentis
In comparison, Lucentis has been proven safe and effective in a number of studies. The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) is a multicenter, double-blind, sham-controlled study that randomly assigned patients with AMD with either minimally classic or occult choroidal neovascularization to receive 24 monthly injections of either 0.3 mg or 0.5 mg of ranibizumab or sham injections.(2) The study included 716 patients at 96 sites. To be included in the study, patients had to meet the following criteria:
Additionally, 24.8 percent of the 0.3-mg group and 33.8 percent of the 0.5-mg group had an improvement in visual acuity of 15 or more letters, compared with 5.0 percent of the sham-injection group. Mean changes in visual acuity were an increase of 6.5 letters in the 0.3- g group, an increase of 7.2 letters in the 0.5-mg group, and a decrease of 10.4 letters in the sham injection group. The increase in visual acuity was maintained at 24 months. Regarding adverse events, presumed endophthalmitis was observed in five patients (1.0 percent), and serious uveitis was observed in six patients (1.3 percent) who received ranibizumab.
Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) is a two-year, multicenter, double-blind study in which patients were randomly assigned in a 1:1:1 ratio to receive monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or monthly sham injections plus active verteporfin therapy.(3) To be included in the study, patients had to be at least 50 years old, have a lesion that was 5,400 μm or less in greatest linear dimension in the study eye, have best-corrected visual acuity of 20/40 to 20/320, have no permanent structural damage to the central fovea, and have had no previous treatment that might compromise assessment of the study treatment.
Of the 423 patients enrolled in the study, 94.3 percent of those given 0.3 mg of ranibizumab and 96.4 percent of those given 0.5 mg of ranibizumab lost fewer than 15 letters, compared with 64.3 percent of patients in the verteporfin group. Additionally, 35.7 percent of those in the 0.3-mg group and 40.3 percent of those in the 0.5-mg group had visual acuity improvements of 15 letters or more, compared with 5.6 percent of the verteporfin group. Mean changes in visual acuity were an increase of 8.5 letters in the 0.3-mg group, an increase of 11.3 letters in the 0.5-mg group, and a decrease of 9.5 letters in the verteporfin group. Two of the 140 patients treated with 0.5 mg of ranibizumab experienced presumed endophthalmitis (1.4 percent), and one experienced serious uveitis (0.7 percent).
Additionally, year one results of the two-year FOCUS study were recently published.(4) In this Phase I/II, multicenter, randomized, single-masked, controlled study, 106 patients received monthly ranibizumab (0.5 mg) injections, and 56 patients received sham injections. Photodynamic therapy was performed seven days before the initial ranibizumab or sham treatment and then quarterly as needed.
To be included in the study, patients had to have primary or recurrent subfoveal CNV that was secondary to AMD, with a total lesion size of 5,400 μm or less in greatest linear dimension, be at least 50 years of age, and have best-corrected visual acuity of 20/40 to 20/320 in the study eye.
At 12 months, 90.5 percent of patients in the ranibizumab group and 67.9 percent of the control patients had lost fewer than 15 letters. The most frequent serious ocular adverse events associated with ranibizumab treatment were intraocular inflammation (11.4 percent) and endophthalmitis (1.9 percent). However, even patients with serious inflammation had better visual acuity outcomes at 12 months than controls.
Switching Patients
Ophthalmologists have embraced both of these drugs for their patients with AMD, which is now considered an epidemic in the developed world. In fact, according to the Beaver Dam Eye Study, approximately one in three people will be affected by AMD to some degree by the age of 75.(5) With patients living longer, more people than ever before will reach the age of 75 years and will be affected by AMD.
The controversy surrounding the choice between Avastin and Lucentis is evident in the recent PAT Mini-Survey conducted by the American Society of Retina Specialists. According to the survey, many ophthalmologists are switching their AMD patients to Lucentis and Avastin. As of September 2006, 70 percent of AMD patients with Medicare and no secondary insurance are being treated with Avastin and 20 percent are being treated with Lucentis. For patients with Medicare and secondary insurance, 49 percent are using Avastin, and 39 percent are using Lucentis.
These numbers will likely fluctuate the longer Lucentis is on the market as reimbursement issues are resolved and physicians have the opportunity to see for themselves if there is much of an efficacy difference when these drugs are compared. More ophthalmologists will move toward Lucentis as they feel comfortable that Lucentis is going to be reimbursed. At the same time, some may move back to Avastin if there is a perception that the two drugs have similar efficacy. For this reason, some ophthalmologists are questioning whether Lucentis is worth the high price tag: Lucentis costs more than $2,000, while Avastin costs between $17 and $50, depending on where you buy it.
Both drugs have their advantages. The primary advantage of Avastin is price, and the primary advantage of Lucentis is support from prospective, randomized clinical trials showing it to be safe and effective. However, the advantage of Lucentis’ clinical trial results is significant; it’s something that we all think about very carefully when we choose one drug over another drug.
Fortunately, a head-to-head comparison of Lucentis and Avastin is under way. The study has been approved by the National Eye Institute, and will begin enrollment in early 2007. We eagerly await the results of this trial, as I believe that this trial, above all else, is a very important public-health study that will have a global impact. After all, in most of the world, Avastin is the only affordable option to prevent blindness from VEGF mediated diseases.
Dr. Rosenfeld is with the department of ophthalmology at Bascom Palmer Eye Institute
in Miami.
1. Bashshur ZF, Bazarbachi A, Schakal A, Haddad ZA, El Haibi CP, Noureddin BN. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular
degeneration. Am J Ophthalmol 2006;142:1-9.
2. Rosenfeld PJ, Brown DM, Heier JS, et al, for the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-1431.
3. Brown DM, Kaiser PK, Michels M, et al, for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-1444.
4. Heier JS, Boyer DS, Ciulla TA, et al, for the FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration. Arch Ophthalmol 2006;124:1532-1542.
5. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933-943.
Author’s Note on Avastin
Since posting the original article on January 31, 2006, I have now posted eleven updates on this important drug for treating age-related macular degeneration. In addition to the posting you are reading, here is a listing (with links) to the others:
Avastin: A New Hope for Treating AMD (January 2006)
Avastin Update: Medicare not Likely to Cover its Use (March 2006)
Avastin Update II: AAO supports Medicare Coverage for Off-label Avastin Use (April 2006)
ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD (May 2006)
Treating AMD with Lucentis and Avastin
While these drugs have revolutionized the treatment of AMD, choosing between them remains a challenge.
Philip J. Rosenfeld, MD, PhD Miami
Both Lucentis (ranibizumab, Genentech.) and Avastin (bevacizumab, Genentech) have successfully been used to treat neovascular age-related macular degeneration. While the Avastin experience has been mainly anecdotal and published as retrospective reviews along with small, short-term prospective studies, the Lucentis experience is supported by extensive clinical trial data. Additionally, Lucentis is approved by the Food and Drug Administration for the treatment of neovascular AMD, while Avastin is used off-label for this indication. On the other hand, Avastin is affordable, while Lucentis’ high price may be out of reach for some patients in the United States and for many more globally. Both drugs have advantages that need to be considered when choosing which one to offer patients.
Early Development
Avastin and Lucentis are derived from the same protein. Researchers at Genentech developed a mouse antibody against vascular endothelial growth factor (VEGF). In the 1990s, they made the decision to go in two different directions with the molecule: to humanize the entire mouse molecule for the systemic therapy of cancer and to humanize and affinity mature one of the binding portions of the molecule, which was one third the size of the whole molecule.
They believed that a smaller molecule would be needed to be effective after being injected into the eye. In theory, a smaller molecule would have better penetration and would cause less inflammation in the eye. Additionally, they were concerned about systemic side effects, and they believed that a smaller molecule would be cleared from the systemic circulation faster. In summary, a smaller molecule would have good opportunity for local effectiveness without any risks of systemic toxicity.
There was parallel development of the two molecules, and Avastin was approved for the treatment of colorectal cancer in 2004, and Lucentis was approved for neovascular AMD in 2006.
Avastin
After Lucentis showed promise for the treatment of AMD and systemic Avastin showed promise for the treatment of neovascular AMD, intravitreal Avastin was used as salvage therapy in patients losing vision despite receiving FDA-approved therapies. While no large clinical studies evaluating Avastin for the treatment of AMD have been conducted, the first prospective study using intravitreal bevacizumab for the treatment of neovascular AMD was recently published. (1) This study was conducted in Lebanon by Ziad Bashshur, MD, and colleagues, who administered an intravitreal dose of 2.5 mg in 17 eyes at monthly intervals for the first three injections. They reported their outcomes at 12 weeks, which was four weeks after the last injection. At 12 weeks, mean and median visual acuity had improved, and there was a marked decrease in the 1-mm central retinal thickness measurement obtained using optical coherence tomography. They researchers observed no ocular inflammation or systemic adverse events.
While these results are promising, this study has several limitations. First, the study included only a small number of patients, and they were followed for only 12 weeks. Additionally, only one dosage was studied and questions persist regarding the optimal dose and dosing interval of Avastin, as well as its safety.
The off-label use of Avastin for the treatment of AMD continues to be controversial, with many practitioners questioning the wisdom of injecting Avastin without large, prospective studies to verify its safety. However, many in the vitreoretinal community perceive Avastin to be safe and its efficacy to be equivalent to Lucentis in most patients. But, the overriding feature of Avastin that continues to fuel its widespread use is its low cost.
Lucentis
In comparison, Lucentis has been proven safe and effective in a number of studies. The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) is a multicenter, double-blind, sham-controlled study that randomly assigned patients with AMD with either minimally classic or occult choroidal neovascularization to receive 24 monthly injections of either 0.3 mg or 0.5 mg of ranibizumab or sham injections.(2) The study included 716 patients at 96 sites. To be included in the study, patients had to meet the following criteria:
- Be at least 50 years old.
- Have a best-corrected visual acuity of 20/40 to 20/320.
- Have primary or recurrent choroidal neovascularization associated with AMD, involving the foveal center.
- Have a type of lesion that had been assessed with the use of fluorescein angiography and fundus photography as minimally classic or occult with no classic choroidal neovascularization.
- Have a maximum lesion size of 12 optic-disc areas with neovascularization composing 50 percent or more of the entire lesion.
- Have presumed recent progression of disease as evidenced by observable blood, recent vision loss, or a recent increase in a lesion’s greatest linear diameter of 10 percent or more.
Additionally, 24.8 percent of the 0.3-mg group and 33.8 percent of the 0.5-mg group had an improvement in visual acuity of 15 or more letters, compared with 5.0 percent of the sham-injection group. Mean changes in visual acuity were an increase of 6.5 letters in the 0.3- g group, an increase of 7.2 letters in the 0.5-mg group, and a decrease of 10.4 letters in the sham injection group. The increase in visual acuity was maintained at 24 months. Regarding adverse events, presumed endophthalmitis was observed in five patients (1.0 percent), and serious uveitis was observed in six patients (1.3 percent) who received ranibizumab.
Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) is a two-year, multicenter, double-blind study in which patients were randomly assigned in a 1:1:1 ratio to receive monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or monthly sham injections plus active verteporfin therapy.(3) To be included in the study, patients had to be at least 50 years old, have a lesion that was 5,400 μm or less in greatest linear dimension in the study eye, have best-corrected visual acuity of 20/40 to 20/320, have no permanent structural damage to the central fovea, and have had no previous treatment that might compromise assessment of the study treatment.
Of the 423 patients enrolled in the study, 94.3 percent of those given 0.3 mg of ranibizumab and 96.4 percent of those given 0.5 mg of ranibizumab lost fewer than 15 letters, compared with 64.3 percent of patients in the verteporfin group. Additionally, 35.7 percent of those in the 0.3-mg group and 40.3 percent of those in the 0.5-mg group had visual acuity improvements of 15 letters or more, compared with 5.6 percent of the verteporfin group. Mean changes in visual acuity were an increase of 8.5 letters in the 0.3-mg group, an increase of 11.3 letters in the 0.5-mg group, and a decrease of 9.5 letters in the verteporfin group. Two of the 140 patients treated with 0.5 mg of ranibizumab experienced presumed endophthalmitis (1.4 percent), and one experienced serious uveitis (0.7 percent).
Additionally, year one results of the two-year FOCUS study were recently published.(4) In this Phase I/II, multicenter, randomized, single-masked, controlled study, 106 patients received monthly ranibizumab (0.5 mg) injections, and 56 patients received sham injections. Photodynamic therapy was performed seven days before the initial ranibizumab or sham treatment and then quarterly as needed.
To be included in the study, patients had to have primary or recurrent subfoveal CNV that was secondary to AMD, with a total lesion size of 5,400 μm or less in greatest linear dimension, be at least 50 years of age, and have best-corrected visual acuity of 20/40 to 20/320 in the study eye.
At 12 months, 90.5 percent of patients in the ranibizumab group and 67.9 percent of the control patients had lost fewer than 15 letters. The most frequent serious ocular adverse events associated with ranibizumab treatment were intraocular inflammation (11.4 percent) and endophthalmitis (1.9 percent). However, even patients with serious inflammation had better visual acuity outcomes at 12 months than controls.
Switching Patients
Ophthalmologists have embraced both of these drugs for their patients with AMD, which is now considered an epidemic in the developed world. In fact, according to the Beaver Dam Eye Study, approximately one in three people will be affected by AMD to some degree by the age of 75.(5) With patients living longer, more people than ever before will reach the age of 75 years and will be affected by AMD.
The controversy surrounding the choice between Avastin and Lucentis is evident in the recent PAT Mini-Survey conducted by the American Society of Retina Specialists. According to the survey, many ophthalmologists are switching their AMD patients to Lucentis and Avastin. As of September 2006, 70 percent of AMD patients with Medicare and no secondary insurance are being treated with Avastin and 20 percent are being treated with Lucentis. For patients with Medicare and secondary insurance, 49 percent are using Avastin, and 39 percent are using Lucentis.
These numbers will likely fluctuate the longer Lucentis is on the market as reimbursement issues are resolved and physicians have the opportunity to see for themselves if there is much of an efficacy difference when these drugs are compared. More ophthalmologists will move toward Lucentis as they feel comfortable that Lucentis is going to be reimbursed. At the same time, some may move back to Avastin if there is a perception that the two drugs have similar efficacy. For this reason, some ophthalmologists are questioning whether Lucentis is worth the high price tag: Lucentis costs more than $2,000, while Avastin costs between $17 and $50, depending on where you buy it.
Both drugs have their advantages. The primary advantage of Avastin is price, and the primary advantage of Lucentis is support from prospective, randomized clinical trials showing it to be safe and effective. However, the advantage of Lucentis’ clinical trial results is significant; it’s something that we all think about very carefully when we choose one drug over another drug.
Fortunately, a head-to-head comparison of Lucentis and Avastin is under way. The study has been approved by the National Eye Institute, and will begin enrollment in early 2007. We eagerly await the results of this trial, as I believe that this trial, above all else, is a very important public-health study that will have a global impact. After all, in most of the world, Avastin is the only affordable option to prevent blindness from VEGF mediated diseases.
Dr. Rosenfeld is with the department of ophthalmology at Bascom Palmer Eye Institute
in Miami.
1. Bashshur ZF, Bazarbachi A, Schakal A, Haddad ZA, El Haibi CP, Noureddin BN. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular
degeneration. Am J Ophthalmol 2006;142:1-9.
2. Rosenfeld PJ, Brown DM, Heier JS, et al, for the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-1431.
3. Brown DM, Kaiser PK, Michels M, et al, for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-1444.
4. Heier JS, Boyer DS, Ciulla TA, et al, for the FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration. Arch Ophthalmol 2006;124:1532-1542.
5. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933-943.
Author’s Note on Avastin
Since posting the original article on January 31, 2006, I have now posted eleven updates on this important drug for treating age-related macular degeneration. In addition to the posting you are reading, here is a listing (with links) to the others:
Avastin: A New Hope for Treating AMD (January 2006)
Avastin Update: Medicare not Likely to Cover its Use (March 2006)
Avastin Update II: AAO supports Medicare Coverage for Off-label Avastin Use (April 2006)
ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD (May 2006)
Avastin/Lucentis Update 4: FDA Approves Lucentis for Treating Wet AMD (July 2006)
Avastin Update 5: NIH Considers Comparing Lucentis and Avastin (August 2006)
Avastin/Lucentis Update 6: Latest Results Published in NEJM and Another Call for a Trial Between Them (October 2006)
Avastin/Lucentis Update 7: BREAKING NEWS – NEI/NIH Will Fund Comparative Study (October 2006)
Avastin/Lucentis Update 8: A Report of the Latest News from the 2006 AAO Meeting (November 2006)
Avastin/Lucentis Update 9: A Disturbing Report about the Upcoming Trial Between Avastin and Lucentis (December 2006)
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