Avastin: A New Hope for Treating AMD
This report was prepared for publication in my Journal on December 31, 2005.
Irving J. Arons
Spectrum Consulting
Over the years, beginning in December 1994 (1-3), I have been reporting on potential laser-based treatments for age-related macular degeneration (AMD); primarily because my specialty was laser technologies and not drugs/pharmaceuticals. However, this past summer, my eyes were opened, as I read a review by Lynne Peterson in Trends-in-Medicine, reporting on what she learned at the July 2005 American Society of Retina Specialists meeting (4), held in Montreal.
First Reports about Avastin
Lynne reported about two drugs from Genentech — Lucentis and — for the first time — its sister drug, Avistan. Both are anti-VEGF agents and have the ability, not only to stop wet AMD cold in its tracks, but to actually improve vision for those afflicted with the disease.
As she wrote, “Word spread like a tsunami through the American Society of Retina Specialists (ASRS) meeting about the newly discovered benefits in wet age-related macular degeneration (AMD) from the off-label – and very inexpensive – use of a chemotherapy agent for colorectal cancer. At the beginning of the meeting, only a handful of doctors knew about intravitreal injections of Genentech’s Avastin (bevacizumab), but by the end of the meeting, most doctors questioned said they plan to go home and try it.”
“In fact, Avastin stole the show from Genentech’s Lucentis (ranibizumab), a fragment of the Avastin molecule that is being developed specifically as an intravitreal injection for AMD. The data presented on Lucentis was outstanding, but it did as much to convince doctors of the value of Avastin as to build anticipation for Lucentis. There have been no studies of Avastin, just case reports and personal experiences, but that was enough to make doctors want to use it – particularly in patients who have failed photodynamic therapy and/or Eyetech’s Macugen (pegaptanib).”
First Reports from the AAO
This piqued my interest, which was soon aroused again as the first reports from the October 2005 American Academy of Ophthalmology (AAO) meeting emerged, especially from the Retina Subspecialty Days presentations. The first report I read was Dave Harmon’s AAO report in his November Ophthalmic Market Perspectives (5), in which his #1 key area of directional shift in the thinking of ophthalmologists was The Avastin Embrace. As he put it, “After years and countless millions spent in development of a new generation of AMD drugs, many of which are still in final stages of FDA trials, the retinal community is most excited about the results from treatment with a low cost drug now designated as a treatment for colorectal cancer. If the Avastin momentum continues, it could reduce the cost of AMD treatment to a small fraction of current amounts and wrench the wind from dozens of new drug development programs.”
Later, in his report on the Retina Subspecialty Day, he wrote: “Record attendance at the Retina Subspecialty Day Meeting underscored excitement and interest in new treatments for retinal disease. Updated clinical data on new drugs and therapies for treatment of AMD garnered the most interest at the two-day meeting. The agenda included the latest clinical data for new drug therapies including Macugen (EyeTech Pfizer), Lucentis (Genentech), and Retaane (Alcon). Also featured were updates in clinical experience with photodynamic therapy (PDT) and several studies of combination PDT and drug therapy.
Lucentis continues to be the most exciting new drug in the development channel. Jeffery Heir, MD, reported that one-year patient data from the Lucentis Marina clinical trial showed that approximately 95 percent of patients treated with the drug lost fewer than 15 letters of visual acuity compared with 62 percent in the control group. On average the patients treated with Lucentis had a significant improvement in visual acuity relative to baseline, whereas the control group experienced a substantial decrease in visual acuity from baseline.
However, another Genentech drug generated the most excitement. Avastin, of which Lucentis is a fragment, has been used in the treatment of colorectal cancer since 2004, and works by blocking the formation of new blood vessels leading to metastasis. Phillip Rosenfeld, MD, PhD, of the Bascom Palmer Eye Institute reported on treatment results using systemic Avastin in salvage patients (patients who had not responded to other drugs). In the spring of 2004, researchers initiated a Phase I/II trial using Avastin which now includes 18 patients followed for 24 months. The results appear to be similar to those of Genentech’s Lucentis, with AMD patients experiencing improvements in vision...
George Williams, MD, cautioned attendees on the impact of high-priced AMD treatments for US patients. Williams reported that with the currently approved medications, the annual cost of AMD therapy in the US could reach $1 billion. While Medicare will cover the majority of these costs, current policies designed to reduce expenses will lead to a 40 percent decrease in Medicare reimbursement for treatment of AMD by 2013. Williams said that this situation places a significant burden on retinal specialists to select treatments that are in the best interest of the patient and society as a whole. “
This was quickly followed by Michael Lachman (of Lachman Consulting LLC) in his EyeQ Report No 2 (6) of the AAO meeting, in which he reported that (the treatment of) AMD was in transition.
As he put it, “Treatment regimens for wet age-related macular degeneration (AMD) are about one year into what will be a period of transition lasting three years or more. With Eyetech and Pfizer’s Macugen about ten months into its US launch, sales have risen steadily and have had a meaningful impact on domestic Visudyne sales. Visudyne is holding up well internationally, where Macugen is generally not yet available. Off-label use of Genentech’s Avastin is also having an impact on both Macugen and Visudyne sales in the US. Meanwhile, Genentech just released impressive clinical results for Lucentis from the pivotal ANCHOR trial, to go along with the previously released impressive results from the pivotal MARINA trial. Genentech plans to file its Biologics License Application (BLA) next month and request priority review. Once Lucentis is approved, as early as H2-06, the impact on both Visudyne and Macugen will be immediate and significant.
The next report that caught my eye was the supplement that accompanied the December 2005 issue of Review of Ophthalmology, entitled AMD 2005: Evolving treatment Options (7), especially the update on Bevacizumab (Avastin) by Philip Rosenfeld, MD, Associate Professor of Ophthalmology at Bascom Palmer Eye Institute.
He wrote about anti-VEGF drugs and Avastin in particular. (He is the foremost investigator into this drug and its applications in treating wet AMD.) But the telling point he made is about the cost differential between Avastin and the other two anti-VEGF drugs, Macugen and Lucentis. It appears that Avastin, which is already FDA approved for use in treating colon cancer, costs about $5.50 per dose, compared to $1000 - $3300 per dose for Macugen (or Lucentis, when it is approved sometime later this year).
On December 30, 2005, Genentech filed for a Biologics License Application (BLA) of Lucentis (8), asking for “priority review” approval, which could come in as little as six months.
Clinical Results
Finally, a report came across my desk from the recent Hawaiian Eye and Retina 2006 meetings held in January in Hawaii. Michael Lachman issued another EyeQ Report (9) stating, More Good News for AMD Patients (and Presbyopes). Two parts of Michael’s report were his highlights: “Highlights of the Retina 2006 program: (1) presentation of additional outrageous Phase III data for Genentech’s Lucentis for wet AMD, (2) growing off-label use of intravitreal Avastin for a number of retinal indications, and (3) diminishing interest in Macugen, Visudyne/PDT, and intravitreal triamcinolone”... and his report on the one-year results of the Genentech pivotal ANCHOR study, comparing Lucentis at two dosage levels to Visudyne/PDT as the control.
The results for Lucentis were outstanding, with Lucentis actually showing significant improvement in vision of 36% to 40%, compared to 6% for Visudyne.
Of the primary endpoint, 94% and 96% of Lucentis patients maintained vision (i.e., a loss of less than 3 lines of visual acuity (VA)) compared to 64% with Visudyne.
Of the secondary endpoints, the aforementioned 3+ lines of vision was achieved for 36% and 40% with Lucentis and only 6% with Visudyne. Changes in VA of 20/40 pre-op to post-op went from 1.4% to 31.4% for 0.3 mg doses and 4.3% to 38.6% for the 0.5 mg dose. Meanwhile, the Visudyne controls only improved from 0% to 2.8%!
There were other significant changes, including severe loss of vision of 0% with Lucentis compared to 13.3% with Visudyne. (For the rest of the results, please see the table on page 2 of the EyeQ Report, and shown below.)
Commenting on the off-label use of Avastin, Lachman noted that since the first announcement by Rosenfeld at the ASRS in Montreal in July, over 5000 invitravitreal injections have been administered to patients in the U.S.
Lachman also commented on the anecdotal uses of both drugs by some physicians who believe that Lucentis might be slightly more effective than Avastin.
The fly in the ointment, however, might depend on reimbursement. As Lachman further noted, “CMS is cracking down on physician reimbursement for intravitreal injections of Avastin. The cost of the drug itself is not reimbursed, although in quantities used for intravitreal injection, the cost is relatively low at $15-75 per dose. Based on the investigational nature of intravitreal Avastin and the lack of supporting clinical data, all 17 Medicare carriers covering all 50 states have issued verbal denials of coverage, and seven carriers covering 12 states have issued written denials. Retina specialists are hoping that the reimbursement situation will improve in the coming months, supported by the near-term publication of a number of peer-reviewed articles, in RETINA and other journals, covering physician-led studies of intravitreal Avastin.”
The Bottom Line
Advances in the treatment of wet AMD are definitely on the horizon. Improvements over current treatments are possible today with the off-label use of Avastin — although reimbursement is definitely a problem, while Lucentis will probably be approved within six months and, will be reimbursable (although at a much greater cost to the Medicare system).
As new events unfold in this story, I will attempt to update the status of both Lucentis and Avastin.
References:
1. “Photodynamic Therapy for Macular Degeneration”, I.J. Arons, Technology Update, Ocular Surgery News, December 15, 1994.
2. “Laser Treatments for AMD Show Promise”, I.J. Arons, Technology Update, Ocular Surgery News, January 15, 2000.
3. “Visudyne Looks Promising for Treating Wet AMD”, I.J. Arons, Retina/Vitreous, Ocular Surgery News, January 15, 2001.
4. “American Society of Retina Specialists, Montreal Canada, July 16-20, 2005", Lynne Peterson, Trends-in-Medicine, July 2005.
5. “New Directions Set at 2005 AAO Meeting”, David Harmon and William Freeman, Ophthalmic Market Perspectives, Market Scope, November 11, 2005.
6. “Ophthalmology Q3-05: IOLs Strong, Refractive Mixed, and AMD in Transition”, Michael Lachman, EyeQ Report No. 2, Lachman Consulting LLC, November 18, 2005.
7. “AMD 2005: Evolving Treatment Options”, Supplement to Review of Ophthalmology, December 2005.
8. “Genentech Announces Filing of BLA for Lucentis”, PRNewswire, December 30, 2005.
9. “Hawaiian Eye and Retina 2006: More Good News for AMD Patients and Presbyopes”, Michael Lachman, EyeQ Report No. 3, Lachman Consulting LLC, January 23, 2005.
Note: Some of the references above, notably the report from the ASRS meeting in Montreal (4) and Dave Harmon's report from the AAO (5) are subscription only. Anyone who would like to see the specific references are urged to email me and I will forward you a saved copy.
Author’s Note on Avastin
Since the original posting on January 31st, I have added three 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 Update: Medicare not Likely to Cover its Use
Avistin Update II: AAO supports Medicare Coverage for Off-label Avistan Use
ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD
Irving J. Arons
Spectrum Consulting
Over the years, beginning in December 1994 (1-3), I have been reporting on potential laser-based treatments for age-related macular degeneration (AMD); primarily because my specialty was laser technologies and not drugs/pharmaceuticals. However, this past summer, my eyes were opened, as I read a review by Lynne Peterson in Trends-in-Medicine, reporting on what she learned at the July 2005 American Society of Retina Specialists meeting (4), held in Montreal.
First Reports about Avastin
Lynne reported about two drugs from Genentech — Lucentis and — for the first time — its sister drug, Avistan. Both are anti-VEGF agents and have the ability, not only to stop wet AMD cold in its tracks, but to actually improve vision for those afflicted with the disease.
As she wrote, “Word spread like a tsunami through the American Society of Retina Specialists (ASRS) meeting about the newly discovered benefits in wet age-related macular degeneration (AMD) from the off-label – and very inexpensive – use of a chemotherapy agent for colorectal cancer. At the beginning of the meeting, only a handful of doctors knew about intravitreal injections of Genentech’s Avastin (bevacizumab), but by the end of the meeting, most doctors questioned said they plan to go home and try it.”
“In fact, Avastin stole the show from Genentech’s Lucentis (ranibizumab), a fragment of the Avastin molecule that is being developed specifically as an intravitreal injection for AMD. The data presented on Lucentis was outstanding, but it did as much to convince doctors of the value of Avastin as to build anticipation for Lucentis. There have been no studies of Avastin, just case reports and personal experiences, but that was enough to make doctors want to use it – particularly in patients who have failed photodynamic therapy and/or Eyetech’s Macugen (pegaptanib).”
First Reports from the AAO
This piqued my interest, which was soon aroused again as the first reports from the October 2005 American Academy of Ophthalmology (AAO) meeting emerged, especially from the Retina Subspecialty Days presentations. The first report I read was Dave Harmon’s AAO report in his November Ophthalmic Market Perspectives (5), in which his #1 key area of directional shift in the thinking of ophthalmologists was The Avastin Embrace. As he put it, “After years and countless millions spent in development of a new generation of AMD drugs, many of which are still in final stages of FDA trials, the retinal community is most excited about the results from treatment with a low cost drug now designated as a treatment for colorectal cancer. If the Avastin momentum continues, it could reduce the cost of AMD treatment to a small fraction of current amounts and wrench the wind from dozens of new drug development programs.”
Later, in his report on the Retina Subspecialty Day, he wrote: “Record attendance at the Retina Subspecialty Day Meeting underscored excitement and interest in new treatments for retinal disease. Updated clinical data on new drugs and therapies for treatment of AMD garnered the most interest at the two-day meeting. The agenda included the latest clinical data for new drug therapies including Macugen (EyeTech Pfizer), Lucentis (Genentech), and Retaane (Alcon). Also featured were updates in clinical experience with photodynamic therapy (PDT) and several studies of combination PDT and drug therapy.
Lucentis continues to be the most exciting new drug in the development channel. Jeffery Heir, MD, reported that one-year patient data from the Lucentis Marina clinical trial showed that approximately 95 percent of patients treated with the drug lost fewer than 15 letters of visual acuity compared with 62 percent in the control group. On average the patients treated with Lucentis had a significant improvement in visual acuity relative to baseline, whereas the control group experienced a substantial decrease in visual acuity from baseline.
However, another Genentech drug generated the most excitement. Avastin, of which Lucentis is a fragment, has been used in the treatment of colorectal cancer since 2004, and works by blocking the formation of new blood vessels leading to metastasis. Phillip Rosenfeld, MD, PhD, of the Bascom Palmer Eye Institute reported on treatment results using systemic Avastin in salvage patients (patients who had not responded to other drugs). In the spring of 2004, researchers initiated a Phase I/II trial using Avastin which now includes 18 patients followed for 24 months. The results appear to be similar to those of Genentech’s Lucentis, with AMD patients experiencing improvements in vision...
George Williams, MD, cautioned attendees on the impact of high-priced AMD treatments for US patients. Williams reported that with the currently approved medications, the annual cost of AMD therapy in the US could reach $1 billion. While Medicare will cover the majority of these costs, current policies designed to reduce expenses will lead to a 40 percent decrease in Medicare reimbursement for treatment of AMD by 2013. Williams said that this situation places a significant burden on retinal specialists to select treatments that are in the best interest of the patient and society as a whole. “
This was quickly followed by Michael Lachman (of Lachman Consulting LLC) in his EyeQ Report No 2 (6) of the AAO meeting, in which he reported that (the treatment of) AMD was in transition.
As he put it, “Treatment regimens for wet age-related macular degeneration (AMD) are about one year into what will be a period of transition lasting three years or more. With Eyetech and Pfizer’s Macugen about ten months into its US launch, sales have risen steadily and have had a meaningful impact on domestic Visudyne sales. Visudyne is holding up well internationally, where Macugen is generally not yet available. Off-label use of Genentech’s Avastin is also having an impact on both Macugen and Visudyne sales in the US. Meanwhile, Genentech just released impressive clinical results for Lucentis from the pivotal ANCHOR trial, to go along with the previously released impressive results from the pivotal MARINA trial. Genentech plans to file its Biologics License Application (BLA) next month and request priority review. Once Lucentis is approved, as early as H2-06, the impact on both Visudyne and Macugen will be immediate and significant.
The next report that caught my eye was the supplement that accompanied the December 2005 issue of Review of Ophthalmology, entitled AMD 2005: Evolving treatment Options (7), especially the update on Bevacizumab (Avastin) by Philip Rosenfeld, MD, Associate Professor of Ophthalmology at Bascom Palmer Eye Institute.
He wrote about anti-VEGF drugs and Avastin in particular. (He is the foremost investigator into this drug and its applications in treating wet AMD.) But the telling point he made is about the cost differential between Avastin and the other two anti-VEGF drugs, Macugen and Lucentis. It appears that Avastin, which is already FDA approved for use in treating colon cancer, costs about $5.50 per dose, compared to $1000 - $3300 per dose for Macugen (or Lucentis, when it is approved sometime later this year).
On December 30, 2005, Genentech filed for a Biologics License Application (BLA) of Lucentis (8), asking for “priority review” approval, which could come in as little as six months.
Clinical Results
Finally, a report came across my desk from the recent Hawaiian Eye and Retina 2006 meetings held in January in Hawaii. Michael Lachman issued another EyeQ Report (9) stating, More Good News for AMD Patients (and Presbyopes). Two parts of Michael’s report were his highlights: “Highlights of the Retina 2006 program: (1) presentation of additional outrageous Phase III data for Genentech’s Lucentis for wet AMD, (2) growing off-label use of intravitreal Avastin for a number of retinal indications, and (3) diminishing interest in Macugen, Visudyne/PDT, and intravitreal triamcinolone”... and his report on the one-year results of the Genentech pivotal ANCHOR study, comparing Lucentis at two dosage levels to Visudyne/PDT as the control.
The results for Lucentis were outstanding, with Lucentis actually showing significant improvement in vision of 36% to 40%, compared to 6% for Visudyne.
Of the primary endpoint, 94% and 96% of Lucentis patients maintained vision (i.e., a loss of less than 3 lines of visual acuity (VA)) compared to 64% with Visudyne.
Of the secondary endpoints, the aforementioned 3+ lines of vision was achieved for 36% and 40% with Lucentis and only 6% with Visudyne. Changes in VA of 20/40 pre-op to post-op went from 1.4% to 31.4% for 0.3 mg doses and 4.3% to 38.6% for the 0.5 mg dose. Meanwhile, the Visudyne controls only improved from 0% to 2.8%!
There were other significant changes, including severe loss of vision of 0% with Lucentis compared to 13.3% with Visudyne. (For the rest of the results, please see the table on page 2 of the EyeQ Report, and shown below.)
Commenting on the off-label use of Avastin, Lachman noted that since the first announcement by Rosenfeld at the ASRS in Montreal in July, over 5000 invitravitreal injections have been administered to patients in the U.S.
Lachman also commented on the anecdotal uses of both drugs by some physicians who believe that Lucentis might be slightly more effective than Avastin.
The fly in the ointment, however, might depend on reimbursement. As Lachman further noted, “CMS is cracking down on physician reimbursement for intravitreal injections of Avastin. The cost of the drug itself is not reimbursed, although in quantities used for intravitreal injection, the cost is relatively low at $15-75 per dose. Based on the investigational nature of intravitreal Avastin and the lack of supporting clinical data, all 17 Medicare carriers covering all 50 states have issued verbal denials of coverage, and seven carriers covering 12 states have issued written denials. Retina specialists are hoping that the reimbursement situation will improve in the coming months, supported by the near-term publication of a number of peer-reviewed articles, in RETINA and other journals, covering physician-led studies of intravitreal Avastin.”
The Bottom Line
Advances in the treatment of wet AMD are definitely on the horizon. Improvements over current treatments are possible today with the off-label use of Avastin — although reimbursement is definitely a problem, while Lucentis will probably be approved within six months and, will be reimbursable (although at a much greater cost to the Medicare system).
As new events unfold in this story, I will attempt to update the status of both Lucentis and Avastin.
References:
1. “Photodynamic Therapy for Macular Degeneration”, I.J. Arons, Technology Update, Ocular Surgery News, December 15, 1994.
2. “Laser Treatments for AMD Show Promise”, I.J. Arons, Technology Update, Ocular Surgery News, January 15, 2000.
3. “Visudyne Looks Promising for Treating Wet AMD”, I.J. Arons, Retina/Vitreous, Ocular Surgery News, January 15, 2001.
4. “American Society of Retina Specialists, Montreal Canada, July 16-20, 2005", Lynne Peterson, Trends-in-Medicine, July 2005.
5. “New Directions Set at 2005 AAO Meeting”, David Harmon and William Freeman, Ophthalmic Market Perspectives, Market Scope, November 11, 2005.
6. “Ophthalmology Q3-05: IOLs Strong, Refractive Mixed, and AMD in Transition”, Michael Lachman, EyeQ Report No. 2, Lachman Consulting LLC, November 18, 2005.
7. “AMD 2005: Evolving Treatment Options”, Supplement to Review of Ophthalmology, December 2005.
8. “Genentech Announces Filing of BLA for Lucentis”, PRNewswire, December 30, 2005.
9. “Hawaiian Eye and Retina 2006: More Good News for AMD Patients and Presbyopes”, Michael Lachman, EyeQ Report No. 3, Lachman Consulting LLC, January 23, 2005.
Note: Some of the references above, notably the report from the ASRS meeting in Montreal (4) and Dave Harmon's report from the AAO (5) are subscription only. Anyone who would like to see the specific references are urged to email me and I will forward you a saved copy.
Author’s Note on Avastin
Since the original posting on January 31st, I have added three 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 Update: Medicare not Likely to Cover its Use
Avistin Update II: AAO supports Medicare Coverage for Off-label Avistan Use
ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD
posted by Irv Arons @ 1:02 PM
1 comments
1 Comments:
It was extremely interesting for me to read that blog. Thanx for it. I like such topics and everything connected to this matter. I would like to read a bit more on that blog soon.
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