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Genentech responds to concerns over curtailed bevacizumab sales
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NEW ORLEANS — A Genentech spokesperson defended the company’s decision to cease selling bevacizumab to compounding pharmacies.
During Retina Subspecialty Day at the American Academy of Ophthalmology meeting, Susan Desmond-Hellmann, MD, MPH, the company’s president of product development, reiterated that the company did not intend to interfere with physicians’ prescribing choice.
Bevacizumab (Avastin, Genentech) has become an increasingly popular choice for age-related macular degeneration, although it is not approved for this use.
“When we made our decision about the compounding pharmacies, our belief then — and our belief now — is that physicians will still be able to obtain Avastin,” she said.
Susan Desmond -Hellmann |
Genentech has cited the U.S. Food and Drug Administration’s concerns over the sterility and packaging of bevacizumab as its primary motivation behind the decision.
“We cannot jeopardize our commitment to tens of thousands of other patients by risking FDA action against us,” Dr. Desmond-Hellmann said.
“We’re willing to do everything possible to make sure patients have access to Lucentis (ranibizumab, Genentech),” she said. Like bevacizumab, ranibizumab inhibits VEGF. However, as physicians at the session pointed out, ranibizumab is much more expensive.
Daniel F. Martin, MD, a member of the session’s panel, questioned Genentech’s refusal to support the upcoming Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) trial, which is expected to evaluate both bevacizumab and ranibizumab in the treatment of AMD. The trial is jointly sponsored by the National Institutes of Health and the National Eye Institute.
“We are the only trial that is sufficiently powered to show a difference,” Dr. Martin said.
Genentech will not support the CATT trial because ranibizumab has already been approved as a safe and effective treatment for AMD, Dr. Desmond-Hellmann said.
“We are challenged by the CATT trial because we feel that the need is met,” she said.
These items appeared originally as daily coverage from the meeting on OSNSuperSite.com. Look for more in-depth coverage of these and other topics in upcoming issues of Ocular Surgery News.
Despite lack of industry support, CATT will continue as planned
In response to inquiries over the status of the much anticipated bevacizumab vs. ranibizumab study, the lead investigator said the study was on track.
Daniel F. Martin, MD, delivered an update on funding for the CATT study at Retina Subspecialty Day. A recently revised Medicare policy will support the use of ranibizumab in the trial, and patients will have no out-of-pocket expense, he said.
Genentech decided in July not to support the study or supply either of the drugs, he said.
“Despite numerous inquiries, we have been told that that decision is irreparable,” Dr. Martin said. However, “we are unaffected by the … decision,” he said, reiterating that CATT is fully funded and ready to begin.
In the study, Dr. Martin and colleagues will prospectively compare the results of 1,200 patients randomly assigned to receive either bevacizumab or ranibizumab. Enrollment is expected to begin in early 2008, with 1-year results released in early 2010.
Analysis of ANCHOR data shows efficacy across all subgroups
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Image: Altersitz K, OSN |
Analysis of ANCHOR data at 24 months showed visual and anatomical benefits of ranibizumab in all subgroups that were studied, one surgeon said.
The data support the earlier positive results of the ANCHOR study that favored ranibizumab over photodynamic therapy at all key outcomes, Jeffrey S. Heier, MD, said at Retina Subspecialty Day.
“I’ve never heard anyone question Lucentis’ efficacy,” he said.
Dr. Heier pointed to “dramatic treatment results” in this “remarkably consistent therapy.”
Compared with PDT, ranibizumab showed a better gain in vision and a threefold greater decline in leakage. The overall treatment benefits were seen across all age groups and lesion sizes, he said.
The ANCHOR study was a multicenter, double-masked, controlled phase 3 study that randomly assigned 423 patients to either verteporfin PDT plus monthly sham or sham verteporfin PDT plus monthly intravitreal ranibizumab, dosed at either 0.3 mg or 0.5 mg.
“Ranibizumab remains a consistent and highly effective treatment,” Dr. Heier said.
Study: Ranibizumab demonstrated continued efficacy at 2 years
Ranibizumab dosed on an as-needed basis showed continued improvement in visual acuity and retinal thickness at 2 years follow-up, according to the results of a study.
Philip J. Rosenfeld, MD, PhD, presented the 2-year data from the PrONTO study (Prospective Optical Coherence Tomography Imaging of Patients with Neovascular Age-Related Macular Degeneration Treated with Intraocular Lucentis) at Retina Subspecialty Day.
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Images: Altersitz K, OSN |
By month 24, retinal thickness had decreased by 215 µm and visual acuity had improved by 11.1 letters, he said.
Patients each received an average of 10 injections during the study period. Dr. Rosenfeld presented one case in which the patient achieved a visual acuity of 20/16 with no additional injections. He then described another patient who received a total of 24 injections over 24 months.
The study included all lesion types across 40 patients who had an average age of 83 years. Surgeons injected ranibizumab at months 0, 1 and 2, at which point 97% of patients were “dry.”
The researchers then monitored the patients and re-treated when patients met certain criteria, including the loss of five letters or more of visual acuity with evidence of subretinal fluid, an increase in central retinal thickness of 100 µm or more on optical coherence tomography (OCT), evidence of new hemorrhage, new classic choroidal neovascularization or detection of fluid on OCT persisting 1 month after injection.
“OCT is always going to see the changes,” Dr. Rosenfeld said. “OCT guided the treatment to preserve the efficacy.”
Dr. Rosenfeld cited the need for a larger prospective study to further evaluate the results.
Bevacizumab’s impact felt despite lack of clinical data
Citing the downturn in sales of Visudyne (verteporfin, Novartis) and Macugen (pegaptanib sodium, Eyetech/Pfizer), a surgeon explained how bevacizumab has greatly affected AMD treatment, even though it is has not gained U.S. approval for treating the disease and there is a lack of clinical trial data to support its use.
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Image: Altersitz K, OSN |
“In 2005 and early 2006, mostly anecdotal reports existed regarding the efficacy of intravitreal bevacizumab for neovascular AMD. However, the favorable short-term clinical efficacy was so apparent that use of intravitreal bevacizumab spread rapidly among the retina community,” David F. Williams, MD, said at Retina Subspecialty Day.
Dr. Williams said there are no data that show the dominance of bevacizumab use to treat neovascular AMD, but indirect evidence can be found in sales trends for other primary treatments that were in use in 2005 when bevacizumab first emerged.
“The cost differential between off-label bevacizumab and the other pharmacological treatments for neovascular AMD was striking,” he said.
From the time bevacizumab efficacy data were introduced by Dr. Rosenfeld until the last quarter of 2006, pegaptanib sales fell 26% while verteporfin sales fell 63%.
In addition, the approval of ranibizumab in July 2006 pushed verteporfin sales down 82% while pegaptanib sales fell 92%.
“The unprecedented growth of off-label bevacizumab as a primary therapy for AMD occurred in the setting of anecdotal reports, reports of non-randomized, non-controlled, small clinical series, and individual personal clinical experience,” Dr. Williams said. “It has persisted in the setting of the availability of a highly efficacious, but expensive, [U.S. Food and Drug Administration-approved] product.”
Dr. Williams pointed to four reasons for this growth: the value of evidence-based medicine, the value of mass clinical experience, pricing of FDA-approved drugs and the power of physician choice.
Patients rate 23-gauge vitrectomy more comfortable than 20-gauge surgery
Patients reported significantly more comfort after 23-gauge vitrectomy as opposed to those who had 20-gauge vitrectomy, one surgeon said.
“Small-incision 23-gauge sutureless vitrectomy systems offer significantly higher comfort for patients than 20-gauge,” Susanne Binder, MD, said at Retina Subspecialty Day.
Dr. Binder presented a prospective study of 60 patients randomized to either 20-gauge or 23-gauge vitrectomy and divided among four experienced surgeons.
Postoperatively, patients reported significantly less pain with the smaller, sutureless system, Dr. Binder said. Visual acuity was not significantly different.
The study looked specifically at the time required to complete the surgery, postoperative pain, IOP, complications, visual acuity and the surgeons’ subjective opinions.
Dr. Binder showed that there were no major complications in the 20-gauge group, but the 23-gauge group had two retinal detachments after hemorrhage combined with hypotony.
Surgeons spent approximately the same amount of time performing the procedures with both systems, but wound opening and closure were quicker with the smaller system while the 20-gauge system took less time to perform the actual vitrectomy. The physicians reported there was a longer learning curve with the 23-gauge system but that instrumentation and manipulation were comparable.
25-gauge vitrectomy yielded higher incidence of endophthalmitis than 20-gauge
The risk of developing postoperative endophthalmitis appears to be higher for patients who undergo 25-gauge vitrectomy compared with those who undergo standard 20-gauge vitrectomy, according to two surgeons.
“Traditionally, the reported incidence rates of endophthalmitis occurring after pars plana vitrectomy are low,” Ingrid U. Scott, MD, said at Retina Subspecialty Day. “One of the major trends in vitreoretinal surgery has been the evolution to small-gauge vitrectomy. A reasonable question is whether the incidence rates reported for endophthalmitis after 20-gauge vitrectomy can be abstracted into small-gauge vitrectomy.”
Dr. Scott and colleagues retrospectively compared rates of postoperative endophthalmitis after 25- and 20-gauge vitrectomy. They identified patients who had undergone vitrectomy between January 2005 and December 2006 and who were subsequently treated for endophthalmitis.
Of 13 patients who developed endophthalmitis, 11 patients underwent 25-gauge vitrectomy and two patients underwent 20-gauge vitrectomy. The resulting endophthalmitis incidence rates were 0.84% for 25-gauge vitrectomy and 0.03% for 20-gauge vitrectomy.
In another study, Richard S. Kaiser, MD, described a retrospective review of 8,601 patients.
“We all agree there are significant benefits to sutureless 25-gauge surgery, both from the patient perspective and from the surgeon perspective, but what we really don’t know a lot about are the complications,” Dr. Kaiser said.
He compared 20-gauge vitrectomy with 25-gauge vitrectomy performed by 18 surgeons from January 2004 to August 2006.
Endophthalmitis presented in one of the 5,498 cases of 20-gauge vitrectomy. Of the 3,103 cases of 25-gauge vitrectomy, endophthalmitis presented in seven cases. The endophthalmitis rates were 0.018% for 20-gauge and 0.23% for 25-gauge.
“Twenty-five-gauge is a terrific procedure, but there are complications that occur,” Dr. Kaiser said. “This is an evolving technique and we definitely need to try to improve it.”
Nonvitrectomizing surgery lessens progression of nuclear sclerosis
Nonvitrectomizing vitreous surgery, defined as epimacular proliferation surgery without intraocular infusion or core vitrectomy, can aid visual improvement by minimizing the progression of nuclear sclerosis, one surgeon said.
“Nonvitrectomizing surgery has prevented the development of nuclear sclerosis based on refractive error measurements and Scheimpflug photography performed postoperatively,” Yasuo Tano, MD, said at Retina Subspecialty Day.
Dr. Tano said nuclear cataract is one of the most common problems seen with vitrectomy for various diseases, and it is almost guaranteed to occur postoperatively in elderly patients. Dr. Tano and colleagues hypothesized that this was caused by either intraocular infusion intraoperatively or a large loss within the posterior vitreous, both of which can be avoided with nonvitrectomizing surgery.
In the 5-year follow-up of 30 eyes of 30 patients, Dr. Tano and colleagues measured the cataractous change with Scheimpflug photography and visual acuity.
The average preop visual acuity was 20/50, and postoperatively it was 20/25, Dr. Tano said. Five years later, 29 eyes (97%) were stable or improved.
“In nonvitrectomizing surgery, there’s no significant difference in nuclear density changes between operated and control eyes,” he said. “Nonvitrectomizing surgery can be carried out successfully. No serious complications have been observed during my 5 years of experience with this technique.”
Non-thermal laser shows promising results for DME
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Image: Loughery J, OSN |
A new non-thermal laser has shown promise in treating a small group of diabetic macular edema patients, one surgeon said.
A.M. Peter Hamilton, MD, presented a preliminary report on 61 patients treated with the non-thermal laser treatment, the Ellex 2RT (Ellex Medical Lasers). He discussed his results at Retina Subspecialty Day.
With this technology, short pulses of laser energy are used to stimulate the retinal pigment epithelium. The 532-nm wavelength used for a duration of 3 nanoseconds creates a 400-µm spot on the pigment epithelium that does not damage the overlying retina, according to Dr. Hamilton.
The researchers looked at 18 patients over the course of 29 treatment sessions, measuring progress with color photography and fluorescein angiography.
The results showed that central macular thickness, as measured on OCT, was decreased by more than 5% in 16 patients, maintained within 5% in seven patients and increased by more than 5% in six patients.
Dr. Hamilton said the advantages of the laser include short exposure time, visual acuity improvements, ability to treat close to the macula, no black holes visible at the time of exposure and good microperimetry.
“We can get right in close to the macula without any fear of causing an enlarging burn,” he said. “Because this laser is so gentle and because it is not compromising the outer part of the retina, we can treat large areas.”
Dr. Hamilton said further study is needed to compare the laser with conventional treatments.
Subretinal implant researchers refine treatment protocol to obtain more reliable data
Future studies of an investigational subretinal implant used to treat retinitis pigmentosa must take into account potential confounding factors that can affect vision testing, according to a speaker.
Data from studies of the implant are becoming more reliable now that these factors have been eliminated, John S. Pollack, MD, said at Retina Subspecialty Day.
The Artificial Silicone Retinal (ASR) implant from Optobionics Corp. might improve vision in patients with retinitis pigmentosa, Dr. Pollack said, although the device has not shown statistically significant improvement in ETDRS chart scores.
In a prospective study, Dr. Pollack and colleagues implanted 20 patients at three study centers with the ASR implant. Specifically, 10 patients received the implant in their right eye and 10 patients received the implant in their left eye.
The ASR, a U.S. Food and Drug Administration investigational device designed to react to light, is 2 mm in diameter and 25 µm thick, Dr. Pollack said. Light stimulates cells that come in contact with the implant, releasing neurotrophic factors and facilitating improved retinal cell function. The researchers implanted the device via vitrectomy with posterior hyaloid removal.
At 1-year follow-up, ETDRS visual acuity improved by 10 letters in 20% of implanted eyes compared with 5% of fellow eyes. But researchers discovered that “potentially confounding factors” such as cataract progression, glare and dilated pupils during vision testing could have produced unreliable outcomes.
“Based on these potentially confounding factors, a phase 2 expansion trial was started 1 year ago. All of these patients had protocol modifications based on these confounding factors,” Dr. Pollack said. For example, only pseudophakic eyes were included in the study, and eyes were undilated during vision testing.
The phase 2 expansion study, undertaken by Hugo Quiroz-Mercado, MD, of Mexico City, includes 12 patients with retinitis pigmentosa. “Elimination of the confounding factors in the Mexico study led to improved reliability of the study,” Dr. Pollack said.
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Image: Hasson M, OSN |
Ranibizumab shown to reduce macular thickness more than bevacizumab
Treating neovascular AMD with ranibizumab resulted in a greater reduction in macular thickness but not a better visual outcome compared with treatment with bevacizumab, according to a speaker.
In an independent retrospective study presented at Retina Subspecialty Day, Adam Martidis, MD, and colleagues reviewed outcomes for 176 eyes treated for neovascular AMD with either intravitreal bevacizumab or ranibizumab. The treatments were administered at baseline and at months 1 and 2, with the data interpreted at month 3. The data were collected from six centers over a 6-month period.
Patients included in the study had a baseline visual acuity between 20/40 and 20/320. None had been previously treated.
At month 3, patients treated with bevacizumab showed a 24.7% decrease in absolute central macular thickness, compared with a 32.9% decrease in patients treated with ranibizumab. Dr. Martidis said the ideal goal for each patient was a 200-µm thick retina. In patients treated with bevacizumab, 70.4% achieved this goal compared with 92.7% of patients treated with ranibizumab, he said.
“What most of us were obviously concerned about, both as physicians and our patients are concerned about, is the visual results. I do emphasize that this study was not powered to achieve statistical significance for vision, and indeed we did not achieve a statistically significant vision change [between the groups],” Dr. Martidis said.
Patients treated with bevacizumab achieved a final visual acuity gain of seven letters vs. six letters for patients treated with ranibizumab. Additionally, 20.9% of bevacizumab-treated patients gained three or more lines compared with 34.2% of ranibizumab-treated patients.
“Both bevacizumab and ranibizumab, I think we would all agree, are effective in the treatment of exudative AMD. In this limited sample size, there is no statistically significant difference in visual outcome between the two. However, there is a statistically significant difference in anatomic advantage in favor of ranibizumab as measured by OCT,” Dr. Martidis said.
Radiation combined with anti-VEGF therapy shows efficacy in wet AMD patients
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Image: Altersitz K, OSN |
A new beta radiation epiretinal therapy, in combination with bevacizumab injections, improved visual acuity in patients with wet AMD, a study showed.
Dr. Heier presented 1-year results of an ongoing multicenter study evaluating the efficacy and safety of NeoVista’s beta radiation epiretinal therapy for wet AMD when used in combination with bevacizumab.
Twenty-seven patients with predominantly classic, minimally classic or occult with no classic choroidal neovascularization received a single-treatment dose of 24-Gy beta radiation through vitrectomy and two injections of bevacizumab. One injection was administered at the time of radiation and the second was administered 1 month later.
Patients averaged 72 years of age and were treated between June 2006 and April 2007.
Visual acuity at baseline averaged 41 ETDRS letters. At 12 months follow-up, patients had improved by 13.1 letters. Additionally, 96% of patients lost less than 15 letters.
Overall, 15% of patients required additional bevacizumab injections, and 12% experienced adverse events, which included retinal tear, retinal detachment, subretinal hemorrhage and vitreous hemorrhage.
“The 1-year data provides important evidence that this novel concomitant treatment approach may provide more sustainable options for those suffering from this degenerative condition,” Dr. Heier said.
“Additional ongoing studies may well confirm the viability of this new therapeutic option for the elderly with wet AMD,” he said.
Patients implanted with telescope prosthesis face rehab challenges
Patients implanted with the Implantable Miniature Telescope face postoperative vision rehabilitation challenges that require in-depth pre- and postoperative training, according to a speaker.
With the Implantable Miniature Telescope, being developed by VisionCare Ophthalmic Technologies, patients perceive different-sized images through each eye and decreased peripheral vision in the implanted eye, Lylas F. Mogk, MD, said.
Additionally, patients will experience decreased contrast sensitivity and increased glare, although these complications are not unique to the Implantable Miniature Telescope, she said. Dr. Mogk based her assertions on previous studies that have been conducted of the device.
“With respect to the disparate images from each eye, VisionCare’s stated rehabilitation goal is for implanted patients to keep both eyes open, suppress the information from one or the other eye, and switch back and forth at will with a small prompt, such as a blink,” Dr. Mogk said. “The ramifications of using each eye separately include loss of depth perception.”
Patients will experience difficulties picking up objects, descending and ascending steps, and moving past or on curved or irregular surfaces, she said.
“This is further exacerbated by the second unique visual challenge, which is decreased peripheral field in the implanted eye,” Dr. Mogk said.
Because the patient uses the implanted eye for details, the fellow eye must be exclusively used for mobility, she explained. Patients may have problems with balance and, therefore, should undergo preoperative training with an external telescope that simulates what they will see with the implant, Dr. Mogk said.
“It’s clear that patient selection is a critical matter,” Dr. Mogk said. “Patients must be willing to work at rehabilitation.”
VisionCare has developed a training protocol for the device, which physicians implanting it are required to implement.
Fundus camera adjusts for eye movement during exam
A new fundus camera provides ophthalmologists with an image of peripheral vision that accounts for eye movement during testing, according to a speaker.
David R. Chow, MD, described the features of the MP-1 Microperimeter (Nidek), which combines digital fundus imaging and computerized perimetry.
“One of the greatest strengths of the MP-1 is its ability to perform wide eye fixation tracking, so the pictures of the patient’s fundus are imaged by an infrared camera, and as the patients’ eye and retina move, the camera alters or adjusts for this 25 times per second,” Dr. Chow said.
The camera determines the fixation of a patient and plots fixation as a function of time.
The MP-1 features multiple modes including a training mode, fixation testing, static microperimetry, peripapillary examination, kinetic microperimetry and feedback examination. In all of the modes, physicians can perform progression analysis, as patients are tested at the same points during subsequent exams.
Pegaptanib shows efficacy in macular edema secondary to CRVO
Administering intravitreal pegaptanib sodium injections appears safe and effective in treating macular edema after central retinal vein occlusion, according to a speaker.
Thomas A. Ciulla, MD, presented the 1-year results of a prospective phase 2 study being conducted by the Pegaptanib in Central Retinal Vein Occlusion (CRVO) Study Group, which is investigating the efficacy of Macugen (pegaptanib sodium, Eyetech/Pfizer) in the treatment of macular edema secondary to CRVO.
“Selective VEGF blockade seems to be a promising approach to the treatment of retinal vascular disease,” Dr. Ciulla said.
The study enrolled 98 patients from 36 centers who had had CRVO for 6 months or less. Specifically, 33 patients in group one were randomly assigned to receive 0.3-mg injections of pegaptanib, 33 patients in group two received 1-mg injections of pegaptanib and 32 patients in group three received sham injections. All groups received treatment every 6 weeks for 30 weeks.
At week 30, 36% of patients in group one, 39% of patients in group two and 26% of patients in group three had an improvement in visual acuity of 15 or more letters. In addition, 9% of group one patients, 6% of group two patients and 31% of group three patients had lost 15 or more letters.
“If we look at the OCT data, we can see the mean change in thickness at the central point, and we can see that there’s an improvement in all the groups, but in the Macugen-treated groups, [there’s] a much more robust improvement,” Dr. Ciulla said. “This change occurs very early, within the first 6 weeks.”
Specifically, 68% of group one patients, 63% of group two patients and 10% of group three patients had a decrease in central retinal thickness of 100 µm or more.
After 42 weeks, patients were eligible for re-treatment based on a 15-letter loss in visual acuity, Dr. Ciulla said. Eight patients in group one, seven patients in group two and two patients in group three required additional treatment. The mean number of additional treatments for the pegaptanib-treated patients was 1.5.
Topical bromfenac effective in improving vision in CME patients
Administering topical bromfenac is as effective as diclofenac sodium and ketorolac tromethamine in improving vision in patients with cystoid macular edema, according to a poster.
David S. Rho, MD, and colleagues at the University of Medicine and Dentistry of New Jersey compared the efficacy of administering topical Xibrom (bromfenac ophthalmic solution 0.09%, Ista Pharmaceuticals) twice daily with administering diclofenac sodium 0.1% four times daily and Acular (ketorolac tromethamine 0.5%, Allergan) four times daily for the treatment of acute pseudophakic CME after uncomplicated phacoemulsification and posterior chamber IOL implantation.
Of 166 patients, 62 patients received bromfenac, 52 patients received diclofenac sodium and 52 patients received ketorolac tromethamine. Patients averaged 75.1 years of age in the bromfenac group, 75.9 years in the diclofenac group and 74.9 years in the ketorolac tromethamine group, according to the poster.
The researchers observed no statistically significant differences between the three treatment groups in baseline or final mean visual acuity or in baseline or final mean ETDRS letters. Patients in all three groups experienced a significant improvement in visual acuity (P < .001)="" and="" etdrs="" letters="">P < .001).="">
In addition, patients treated with bromfenac had a significantly better mean letter gain than patients treated with ketorolac tromethamine (P = .036), according to the poster.
“Bromfenac-treated patients had slightly better mean final VA and mean final letters than patients treated with either ketorolac or diclofenac, though these findings did not reach statistical significance,” the authors said.
“No serious adverse reactions were reported in this study,” they noted.
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