Vision Loss With Lucentis
Study: Data Point to Geographic Atrophy.
JERRY HELZNER, SENIOR EDITOR
■ In the pivotal phase 3 MARINA and ANCHOR trials for Lucentis, the great majority of patients showed improved or stable vision. However, 9% of the patients in the MARINA trial and 10% of the patients in the ANCHOR trial lost 15 letters or more after 2 years of treatment with the drug.
A team of investigators headed by Philip Rosenfeld, MD, PhD, of the Bascom Palmer Eye Institute initiated a study to attempt to determine why a small minority of patients did so poorly with Lucentis therapy.
In a poster presentation at the 2007 ARVO meeting in May, the investigators found that "while ranibizumab therapy results in similar decreases in the area of CNV leakage in >15-letter losers and >15-letter gainers, there is a paradoxical increase in total lesion area in >15-letter-losers compared to >15-letter-gainers. "According to the reading center, an increase in total lesion area without an increase in CNV leakage suggests that the change in lesion area is the result of an increase in fibrosis, blood, serous pigment epithelial detachment (PED), blocked fluorescence, geographic atrophy, or a combination of those features.
"Because the area of fibrosis, blood, and PED did not significantly differ between the 2 groups, the most likely cause of vision loss is an increase in the area of geographic atrophy — a feature of dry AMD that could increase in area as part of disease progression."
The investigators do not believe the treatment caused the geographic atrophy, because the visual acuity (VA) improvement in the MARINA and ANCHOR trials was sustained through 2 years while receiving monthly injections of Lucentis. If Lucentis was in any way responsible, they would have expected a loss of efficacy over time. The investigators concluded that VA loss among patients receiving Lucentis could be linked to progression of dry AMD once neovascularization has been arrested.
The investigators are now reviewing the color photographs of patients in the MARINA and ANCHOR studies to assess the change in geographic atrophy over 2 years.
|■ OSI exits eye research. OSI Pharmaceuticals, Inc., which owns and markets Macugen therapy for wet AMD in partnership with Pfizer, has entered into an agreement with Ophthotech Corporation of Princeton, NJ, to divest its anti-platelet-derived growth factor (PDGF) aptamer research program.|
Under the terms of the agreement, OSI will transfer to Ophthotech all rights in the PDGF aptamer program, including rights to its preclinical compound E10030, in exchange for an upfront cash payment, an equity interest in Ophthotech, and potential future milestones and royalties. Financial terms of the agreement have not been disclosed.
In preclinical studies, E10030 demonstrated the potential to regress neovascularization when used in combination with a VEGF inhibitor. OSI elected to suspend further research on this compound in connection with its decision to divest its eye-disease business.
OSI CEO Colin Goddard, PhD, said the company would have preferred to divest its entire eye-disease business in a single transaction. Goddard now believes that the company's Macugen-related assets will be sold before the end of this year.
■ Lucentis sales steady. Genentech reported that sales of Lucentis, the company's breakthrough treatment for wet AMD, topped the $200 million mark again in the second quarter of the year. Sales of the drug amounted to $209 million, almost matching the $211 million recorded in the first quarter.
The company said sales of Lucentis would have been higher except for the fact that the related and less expensive drug Avastin continues to be used off-label to treat wet AMD and other retinal diseases.
■ VEGF Trap in phase 3. Regeneron Pharmaceuticals, Inc. and Bayer HealthCare AG have initiated a phase 3 study of the VEGF Trap-Eye in wet AMD. The study will be a non-inferiority comparison of the VEGF Trap-Eye and Genentech's Lucentis, the leading treatment for wet AMD. This trial, known as VIEW 1 (VEGF Trap: Investigation of Efficacy and safety in Wet age-related macular degeneration), is the first study in the companies' phase 3 global development program in wet AMD, which is planned to be carried out in the United States, Europe, and other parts of the world.
The randomized, double-masked study is expected to enroll approximately 1200 patients in more than 200 centers throughout the United States and Canada. The study will evaluate the safety and efficacy of the VEGF Trap-Eye at doses of 0.5 mg and 2.0 mg administered at 4-week dosing intervals and 2.0 mg at an 8-week dosing interval, compared to 0.5 mg of Lucentis administered every 4 weeks, consistent with its labeled dosing schedule.
■ NICE favors Lucentis. The UK's National Institute for Health and Clinical Excellence (NICE), which has influence over the country's National Health Service as to which drugs are approved or denied reimbursement, has recommended the use of Lucentis for wet AMD patients with "severe" vision loss. NICE also guided doctors away from prescribing rival drug Macugen.
Patient advocates are challenging the decision, claiming that NICE wants to restrict the use of Lucentis to only those patients who have already suffered major vision loss. NICE recommends that Lucentis be used only in "the better-seeing eye."
■ Othera drug trial. Othera Pharmaceuticals, Inc., said that the first patient has been dosed in the OMEGA (OT-551 Multicenter Evaluation of Geographic Atrophy) phase 2 trial, a 198-patient study of OT-551 eyedrops as a treatment for geographic atrophy (GA), the advanced form of dry AMD. Othera believes that OT-551 could represent the first effective treatment for this chronic, degenerative disease that currently affects approximately 1 million elderly Americans.
"I have been interested in dry AMD for 20 years and it's been very lonely," said Paul Sternberg Jr., MD, chairman of Vanderbilt Eye Institute, referring to the fact that until recently, despite its serious nature and prevalence, the need for long and expensive trials meant almost no treatments have been investigated for GA.
Dr. Freund's Rx for Type 3 CNV
Avastin and Lucentis Prove Highly Effective.
JERRY HELZNER, SENIOR EDITOR
■ Little more than a decade ago, type 3 neovascularization, also known as retinal angiomatous proliferation, commonly known as RAP, was first identified as a specific form of neovascularization. Given its brief history, it is no surprise that retina specialists have been grappling with such issues as how the type 3 vessels originate and how to best eliminate them.
Type 3 disease represents about 15% of all neovascular AMD and is typically found in patients who are Caucasian and older than the general AMD population. Type 3 lesions found in 1 eye almost always soon progress to the fellow eye.
|Correction: In the article "Nonmydriatic cameras in retinal practice," published in the July/August 2007 edition of Retinal Physician, the Automated Retinal Imaging System (ARIS, Visual Pathways, Prescott, AZ) was omitted.|
The ARIS offers automated fundus imaging plus the ability to acquire infrared, red, red-free, and color images in under 15 seconds. The camera is available in 2 models, the ARIS 70 and the ARIS 110, which, respectively, offer target positioning in order to cover 70° and 110° on the retina. The ARIS also maintains pupil alignment, focus, and tracking throughout the imaging process. Furthermore, the cameras provide auto-fundus focus, exposure, and illumination with each 30° image.
The cameras' telecentric optics ability finds spherical refractive errors automatically, and allows for dynamic viewing of the retina using several trademarked features, including ConstantBaseStereo, Red/Green ColorOptimizer, and BiochromaticImageNavigation. Finally, the ARIS cameras are both telemedicine-ready and are DICOM and PACS-conformant.
At the recent Retinal Physician Symposium, K. Bailey Freund, MD, of Vitreous-Retina-Macula Consultants of New York, who has done significant work with type 3 patients, not only offered compelling evidence that type 3 disease begins in the choroid, he also offered a treatment regimen that he has been using consistently and with great success over the past 2 years.
Though the origin of type 3 disease does not affect Dr. Freund's suggested treatment regimen, he has used extensive OCT imaging on numerous patients to determine that it is the early formation of retinal choroidal anastomosis that is the "spark of life" for type 3 lesions. He says that his reading of typical type 3 OCT images "looks very suggestive for neovascularization originating from the choroidal circulation" and invading the retina from below.
In regard to treatment approaches, Dr. Freund reports that a combination of intravitreal triamcinolone to reduce the intraretinal cyst, followed a week later with standard-fluence PDT, produced excellent short-term results, with 92% of patients demonstrating stable or improved vision with an average of 2 treatments in the first year.
"Unfortunately, despite the sequence approach, the need for repeated treatments still led to collateral damage in the form of atrophy in many of these patients," Dr. Freund told his audience.
In 2005, Dr. Freund began using Avastin (and subsequently Lucentis) in type 3 patients in order to avoid the atrophy and collateral damage associated with other treatments. Of the first 23 type 3 patients treated with Avastin, 9 had pigment epithelial detachment (PED) and almost half of the patients had lost the central vision in the fellow eye. Eleven of the patients had already had other treatments, primarily triamcinolone and PDT, with 3 of the patients having received 5 or more rounds of PDT.
At 1 month after treatment with Avastin, improvements in both OCT measurement and vision were noted. By 3 months and after an average of 2 treatments, all the PEDs had resolved. No complications were observed.
Dr. Freund has since further refined his first-line type 3 treatment regimen. He suggests either an initial Avastin or Lucentis injection (he finds them equally effective), with OCT follow-up at 5 weeks, then another injection, with OCT imaging again at 7 weeks. He typically "injects and extends" until a maintenance injection can be given every 11 weeks.
"This approach allows for fewer office visits, better visual results and greater compliance than with combination therapy, with [Avastin] drug costs of only about $100 a year," Dr. Freund asserted. "After years of frustration, I'm happy to finally be able to offer my [type 3] patients truly effective treatment which preserves their vision and quality of life."
|■ Allergan grant program. Allergan, Inc. is currently accepting applications for the Allergan Horizon Grant Program. Recognizing the increased competition academic institutions are facing for funding in ophthalmology, Allergan initiated the Allergan Horizon Grant Program in 2006 to provide awards to academic medical institutions that support fellows seeking careers in academic medicine.|
Over the course of the program, Allergan plans to contribute $1 million to support fellowship programs that conduct clinical research in the diagnosis or pharmacological treatment of glaucoma, and corneal, and retinal diseases. Last year, Allergan awarded 10 grants to 13 ophthalmology programs. Grant applications should be submitted by the department chair, division chief, or fellowship director of the academic institution and must be received by Allergan Medical Affairs, 2525 Dupont Drive, Irvine, CA 92612, no later than Sept. 28, 2007.
■ Visudyne sales rise. QLT Inc., the developer of Visudyne photodynamic therapy for the treatment of wet AMD, reported US Visudyne sales of $10.3 million for the second quarter of 2007, up approximately 23% from the $8.4 million reported for the year's first 3 months.
In a related development, QLT has taken a charge of $109.9 million in response to an adverse ruling by the US District Court in a patent ownership suit brought by the Massachusetts Eye and Ear Infirmary (MEEI). The Court ruled that QLT owed MEEI past and future royalties, plus interest and court costs, as an equitable settlement for the role of MEEI in the development of Visudyne. QLT said it expects to appeal the decision.
■ AMO withdraws offer for B&L. Facing opposition from one of its own major shareholders, Advanced Medical Optics (AMO) has withdrawn its $75 a share offer for Bausch & Lomb. B&L will be acquired by private equity firm Warburg Pincus for $65 a share if B&L shareholders vote to approve the deal.
ValueAct Capital, which owns more than 12% of AMO shares, contended that a B&L acquisition would require AMO to take on too much debt and would be difficult to integrate into an AMO corporate structure that is still integrating its recent VISX and IntraLase acquisitions. RP