Avastin/Lucentis Update 8: A Report of the Latest News from the 2006 AAO Meeting

This update on the current status of Avastin and Lucentis, as reported at the recent American Academy of Ophthalmology meeting held in Las Vegas, is presented courtesy of Michael Lachman of Lachman Consulting LLC. His complete report from the AAO meeting, including his update on refractive surgery, is contained in his EyeQ Report No. 9, and can be read in its entirety by clicking on the contained web link.

Avastin and Lucentis: New Treatments of Choice for Wet AMD

Since the FDA approval on June 30, 135,000 doses of Lucentis (ranibizumab) have been administered to over 48,000 AMD patients, according to George Williams, MD speaking at an AAO press conference.

At the Retina Subspecialty Day, Philip J. Rosenfeld, MD, PhD provided an update on the off-label use of intravitreal Avastin (bevacizumab).

Intravitreal Avastin for wet AMD is currently being reimbursed in 48 out of 50 states; the Medicare carrier for Nebraska and Kansas is the only one that is not currently providing coverage for this treatment. In the year- end-half since intravitreal Avastin was first used to treat AMD, numerous investigator-led studies have been initiated. So far in 2006, there are over 60 PubMed references to intravitreal Avastin. At AAO, there were 22 posters, 4 papers, and an instructional course covering this topic. So far, intravitreal Avastin has been shown to be safe, with no indication from available studies or surveys of toxicity, significant inflammation, or signals of systemic adverse events. In terms of efficacy, Avastin is decreasing retinal thickness on OCT and providing modest improvements in visual acuity for a number of proliferative/ exudative retinal conditions.

A snapshot of Avastin and Lucentis usage during September 2006, based on survey responses of 227 US-based ASRS members, was presented by Dr. Rosenfeld. The “PAT Mini-Survey” was conducted by Robert Mittra, MD and John Pollack, MD. Retina specialists were presented a list of AMD treatments asked which one they usually recommend to patients with neovascular AMD:

• For patients that have Medicare but no secondary insurance, 70% of physicians usually recommend Avastin, 20% recommend Lucentis, and 7% recommend one of these drugs in combination with PDT. Only 3% usually recommend other treatments, including Macugen and PDT, alone and in combination.
• For patients that have Medicare with secondary insurance, 49% of physicians usually recommend Avastin, 39% recommend Lucentis, and 7% recommend one of these drugs in combination with PDT. Only 5% usually recommend other treatments, including Macugen and PDT, alone and in combination.

There are two key takeaways from these survey results. First, Genentech’s two anti-VEGF products have almost completely supplanted both Visudyne/PDT and Macugen as the preferred treatments for wet AMD. Second, even for fully insured patients, as of September, Lucentis had not replaced Avastin as the preferred treatment. Dr. Rosenfeld said that these survey results surprised him, because it had been assumed by many that once Lucentis received FDA approval and Medicare reimbursement was established, usage would shift quickly from Avastin to Lucentis, particularly for patients with secondary insurance. He noted that these survey results were from September, and that Lucentis usage has likely increased since then. (Indeed, some retina specialists with whom we spoke at AAO pegged the current relative usage of Lucentis at 60-80%.) Dr. Rosenfeld’s conclusion: “Money matters,” and because there is a perceived equivalence between these two drugs, cost weighs heavily as a factor.

The experience to date from 1,374 treatments with intravitreal Avastin at the New York Eye and Ear Infirmary was reported in a scientific poster. Patients have been treated for choroidal neovascularization, neovascular glaucoma, and macular edema. So far, among AMD patients treated, 38% have gained three or more lines of visual acuity, another 34% have at least maintained vision, and 28% have lost 1-2 lines of VA. Among macular edema patients, 87% have improved VA by at least one line. Among neovascular glaucoma patients, regression of rubeosis was noted within one week. There have been no reported cases of endophthalmitis or retinal detachment, and there have been three cases of mild inflammation that resolved.

NEI/NIH to Sponsor Head-to-Head Study of Lucentis and Avastin

In early October, the National Eye Institute (NEI) of the National Institutes of Health (NIH) announced that it will fund a new multicenter clinical trial to compare Lucentis and Avastin for the treatment of advanced AMD. During the Subspecialty Day program, study chairman Daniel Martin, MD provided an overview of the study, entitled CATT (Complications of Age-Related Macular Degeneration Treatment Trials). The study will enroll about 1,200 patients with newly diagnosed AMD, randomly assigned to one of four groups: (1) Lucentis with four week dosing; (2) Avastin with four week dosing; (3) Lucentis with variable dosing; and (4) Avastin with variable dosing. The regimens are based upon the fact that Avastin is generally given on a variable basis and Lucentis has only been formally tested in a fixed regimen. The main objective will be changes in visual acuity, with secondary objectives including change in lesion size, fluid found in optical coherence tomography and cost, which he emphasized is not the sole purpose of the study.

The study will follow patients for two years and will take about four years to complete. Enrollment is scheduled to begin in early 2007, and one year follow-up data will be reported in 2009. The study will be conducted in 40 centers in the US; 20 have already been selected, and 20 additional centers will be selected by early 2007. NEI/NIH is emphasizing that this is more than just a cost study, and that the primary goals are to better understand the safety and efficacy of intravitreal Avastin and to develop better dosing/ re-treatment guidelines for both drugs. Q

Economic Analyses: Cost Effectiveness of AMD Therapies

Some interesting data points regarding the growth in utilization of retinal services and the highly variable cost of AMD treatment were highlighted by William L. Rich III, MD, the AAO’s Medical Director for Health Policy, at an evening symposium on AMD treatment strategies:

• Between 2001 and 2004, the number of intravitreal injections in the US grew from about 4,500 to about 83,000.
• Between 1999 and 2004, the number of OCT diagnostic exams increased twenty-fold, from 153,000 to 3.11 million.
• Total two-year costs of AMD treatments, including products and services: Avastin $2,037, Visudyne $11,162, Macugen $27, 276, and Lucentis $67, 128.

A rigorous analysis to determine the relative cost of a line of vision in AMD was reported in a scientific poster by William Smiddy, MD of Bascom Palmer. Outcomes data was compiled from a number of published studies, including TAP, AREDS, and ETDRS. Costs were inclusive of office visits, diagnostic testing, and treatments. Results were reported in terms of cost per line- ear of vision saved. Among AMD treatments that have been available for some time, approximate costs per line-year saved were as follows: Juxtafoveal or subfoveal laser: $176; PDT for classic lesions: $448; PDT for occult lesions: $551; PDT plus IVTA; $66; Macugen: $1,248; and vitamins $473. Newer treatments (Lucentis and Avastin) were given a more cursory analysis, due to the relative lack of data available. Initial estimates of cost per line-year of vision saved for Lucentis and Avastin were $900 and $60, respectively. Based on this analysis, Avastin is the most cost-effective AMD treatment currently available (15x more cost effective than Lucentis), and Macugen is the least cost effective.

In order to emphasize the significant difference in cost between Lucentis and Avastin, Retina Subspecialty Day panel moderator H. Richard Johnson, MD posed the rhetorical question, "Given the number of children that could be immunized with the savings from one Avastin treatment, can you justify the use of Lucentis?" Q

Diabetic Retinopathy: Highlighting Advances in Pharmaceutical and Laser Treatment

Lucentis and Avastin Show Promise for Diabetic Retinopathy and Diabetic Macular Edema

Because of the success of anti-VEGF agents Lucentis and Avastin in treating neovascular AMD, they are also being studied in diabetic retinal diseases. Results so far are very encouraging. The following paragraphs highlight presentations of interest from the Retina Subspecialty Day program and the scientific poster session. Peter Campochiaro, MD reported on a prospective, open label Phase I pilot trial of Lucentis in 20 eyes of 20 patients with severe DME at The Johns Hopkins University. The vast majority of eyes in the study (18/20) had already been treated with focal laser and/or intraocular steroids. Patients received five intravitreal injections of Lucentis: an initial injection plus repeat doses at months 1, 2, 4, and 6. Lucentis treatments were well tolerated, and produced marked improvement in DME symptoms. Median excess foveal thickness was reduced by 300μm (97% reduction) at month 7 and by 240μm (77% reduction) at month 12, which was a full six months after the last Lucentis injection. Median visual acuity was improved by 10 letters at month 7 and by 7 letters at month 12. Robert L. Avery, MD discussed his experience with Avastin for proliferative diabetic retinopathy (PDR). Avastin has a rapid anatomic effect in eyes with PDR, although neovascularization recurs after a variable period of time and re-treatment is needed within months after the initial dosing. Dr. Avery also stressed the value of intravitreal Avastin as an adjunct to vitrectomy surgery for treatment of severe PDR; administered several days before surgery, it appears to be effective in reducing intraoperative bleeding.

John Mason III, MD reported on results with intravitreal Avastin in 39 eyes of 34 patients with refractory DME. These patients had already undergone previous treatment with focal laser, intravitreal steroids, or vitrectomy with ILM peeling. Short term results were favorable for this challenging group. Mean acuity at baseline and at one and three months was 20/111, 20/87, and 20/89, respectively. Mean central macular thickness at baseline and at one three months was 357μm, 308μm, and 309μm, respectively.

Again, thank you Michael Lachman, for allowing us to reproduce a significant part of your AAO Report. To see his EyeQ Report No. 9 in its entirety, please click on the web link for the report.

Author’s Note on Avastin

Since posting the original article on January 31, 2006, I have now posted nine 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)

Newer Update:

Avastin/Lucentis Update 9: A Disturbing Report about the Upcoming Trial Between Avastin and Lucentis (December 2006)