AMD Drug Helps 95% of Patients
Lucentis Shows Impressive Results in Phase 3 Trial.
Genentech, Inc. announced that the phase 3 MARINA clinical study of the investigational drug Lucentis met its primary efficacy endpoint of maintaining vision in patients with wet AMD. In a preliminary report on study results, the company said that approximately 95% of patients maintained or improved vision (defined as a loss of less than 15 letters in visual acuity) at 1 year when treated with Lucentis injections compared to approximately 62% of those treated in the control arm.
Patients treated with Lucentis for 12 months had, on average, a significant improvement in visual acuity compared to their visual acuity at study entry, an important secondary endpoint, while the control group demonstrated a substantial decrease in mean visual acuity from baseline to 12 months. More complete 1-year data from the trial will be presented at the 23rd Annual Meeting of the American Society of Retina Specialists (ASRS) this summer.
The Lucentis data were by far the most impressive to come from any phase 3 study of a therapy for wet AMD. The stock of Eyetech Pharmaceuticals, the developer of the already-approved wet AMD drug Macugen, dropped about 45% to $12.95 a share on May 24, the day after the Lucentis results were announced. In phase 3 trials, Macugen was able to improve visual acuity in only a small percentage of patients. However, in a statement Eyetech noted that data on ongoing Lucentis trials are incomplete and that the patient populations in the clinical studies for the 2 drugs may not be comparable.
"These Lucentis data exceeded our expectations because they show, for the first time in a phase 3 trial, a statistically significant improvement in vision for patients in a disease that has remained chronic and progressive despite current treatment options," said Hal Barron, MD, Genentech senior vice president, development and chief medical officer.
Genentech said a preliminary analysis of the data showed that adverse events were similar to those seen in earlier trials of Lucentis. Common side effects occurring in the Lucentis arms more frequently than in the control arms were mild to moderate and included conjunctival hemorrhage, eye pain, and vitreous floaters. Serious ocular adverse events occurring more frequently in Lucentis-treated patients were rare (<1%) and included uveitis and endophthalmitis. There appeared to be no imbalance in serious nonocular adverse events.
In another Lucentis clinical trial, Genentech said that the phase 1/2 FOCUS study of the drug met its primary efficacy endpoint of maintaining vision in patients with wet AMD when used in combination with Visudyne photodynamic therapy (PDT). Genentech said that approximately 90% of patients maintained or improved vision when treated with the combination of Lucentis and PDT, compared to approximately 68% of those treated in the control arm of PDT alone. Patients treated with Lucentis plus PDT at 12 months had, on average, a significant improvement in visual acuity compared to visual acuity at study entry, an important secondary endpoint, while the PDT-alone group demonstrated a decrease in mean visual acuity from baseline to 12 months.
A preliminary analysis of the FOCUS data showed there was an increased risk of uveitis in patients treated with Lucentis in combination with PDT compared to patients treated with PDT alone. An amendment to the study protocol was made after data-safety-monitoring identified this imbalance.
Lucentis is a humanized antibody fragment developed at Genentech and designed to bind and inhibit Vascular Endothelial Growth Factor A (VEGF-A), a protein that is believed to play a critical role in angiogenesis.
The MARINA study is a phase 3 clinical trial of 716 patients in the United States with minimally classic or occult wet AMD who were randomized 2:1 to receive intravitreal Lucentis injections or a control regimen. The control regimen consisted of a sham injection. Patients treated with Lucentis were further randomized to receive either a 0.3 mg or 0.5 mg dose of Lucentis once a month for 2 years. Results from the phase 3 ANCHOR study of Lucentis, comparing the effectiveness of 2 different doses of the drug, are expected to be released in the fourth quarter of 2005. Some industry analysts anticipate that Lucentis could be approved by the FDA sometime late next year. Novartis Pharmaceuticals is Genentech�s partner for the international marketing of Lucentis.
In the May/June Issue of Retinal Physician, the article "Verteporfin Patient Management Update" by Caroline R. Baumal, MD, should have stated that verteprofin is the only photodynamic agent thus far approved to treat CNV in ophthalmology.
Study: Macugen Effective
Treatment Reduced Key Signs of the Disease.
Eyetech Pharmaceuticals, Inc. said that imaging data from a phase 2 study using Macugen therapy for diabetic macular edema (DME) showed a reversal of capillary microaneurysms, retinal ischemia and neovascularization all important signs of diabetic retinopathy.
In the study, researchers conducted a retrospective analysis of 69 patients who had recognized and gradable diabetic retinopathy at both baseline and week 36. Patients treated with Macugen 0.3 mg therapy showed an improvement in the ETDRS diabetic retinopathy severity scale, a standard for monitoring the progression of retinopathy. At week 36, 11 of the 39 Macugen-dosed patients showed improvement of greater than or equal to 1 step vs. 4 of 30 in the sham group. In addition, 5 0f the 39 Macugen patients showed an improvement of more than 2 steps at week 36 compared to 1 of 30 in the sham group.
Macugen is already approved for the treatment of wet AMD.
"Researchers reviewed photographs of the retina and noted evidence of regression of retinal neovascularization and other signs of diabetic retinopathy in patients treated with Macugen. We also found an improvement on the diabetic retinopathy severity scale, which suggests that Macugen may have helped slow or even reverse the progression of the disease," said Larry Singerman, MD, clinical professor of Ophthalmology at Case University School of Medicine and president of Retina Associates of Cleveland. "While no final conclusions can be drawn from these preliminary and limited data as to the efficacy of Macugen in diabetic retinopathy, we are encouraged by the potential implication of these findings, which are consistent with our current understanding of the role of VEGF in diabetic retinopathy," he concluded.
As previously announced, Eyetech and its partner Pfizer plan to conduct a pivotal phase 2/3 DME clinical trial that will include the diabetic retinopathy score as a prespecified secondary endpoint. This trial is expected to begin in the second half of 2005.
In a related development, Health Canada granted approval for Macugen for the treatment of subfoveal choroidal neovascularization secondary to wet AMD. Eyetech and Pfizer copromote Macugen in the US. Eyetech has granted Pfizer the exclusive rights to commercialize Macugen in countries outside the US, including Canada, pursuant to a royalty-bearing licensing agreement.
Also, Eyetech has raised its projection for Macugen sales for all of 2005 from a range of $135 to $150 million to a range of $175 to $190 million.
The company said that 99 of its top 100 Macugen accounts have already reordered the product.
Retaane is "approvable." Alcon, Inc. said that the FDA recently issued an approvable letter for its New Drug Application (NDA) for Retaane 15 mg, an investigational treatment for preserving the vision of patients with wet AMD.
Industry analyst Ted Huber of Wachovia Securities said final approval will almost certainly require another clinical study.
Alcon said it will meet with the FDA to discuss the approvable letter, the clinical studies submitted with the NDA and other ongoing clinical studies for Retaane to determine the steps necessary to gain final approval for the wet AMD indication.
"We believe that Retaane suspension has a positive impact on the vision of patients with AMD. As part of our mission to preserve and restore vision, we are continuing with all of our development efforts for this drug, which we believe will ultimately lead to approval," said Stella Robertson, PhD, Alcon vice president, ophthalmology research and development.
Retaane is administered with a blunt-tipped, curved cannula to deliver the drug behind the eye without puncturing the eyeball. Retaane is administered once every 6 months. No clinically relevant side effects related to the medication or application procedure were reported in the study.
Alcon has conducted extensive clinical research into Retaane over the last 5 years. The company has reported clinical study results from 2 pivotal studies that formed the basis of its clinical package for its NDA. The first study demonstrated that after 1 year 79% of patients treated with Retaane maintained their vision, compared to 53% of those who received a sham application. The second study demonstrated that after 1 year the visual outcomes in patients who received Retaane were not statistically different from those of patients who received photodynamic therapy with Visudyne.
ASCs Win Major Victory
But Some Retinal Procedures Still Await Approval.
The Center for Medicare and Medicaid Services (CMS) has restored to the ambulatory surgery center (ASC) procedures list 95 of the 100 services and all of the ophthalmic surgical codes that were proposed for deletion late last year. This reversal in CMS policy is consistent with the recommendations of the Ophthalmic Outpatient Surgery Society (OOSS), the American Academy of Ophthalmology (AAO) and the American Society of Cataract and Refractive Surgery (ASCRS). The views of these organizations were presented to CMS in formal comments to and meetings with the agency.
In November 2004, CMS had proposed to "update" the ASC procedures list by adding 25 additional ASC procedures, but deleting 100 service codes from, the current list. Had the proposal been finalized as proposed, Medicare-certified ASCs would no longer receive facility payments for 16 ophthalmic surgical procedures, including: 68340 (repair of sympblepharon); 11444, 11446, and 11644 (lesion excisions); 13131, 13132, and 13152 (repairs of wound or lesion); 14000, 14060, and 14061 (skin tissue rearrangements); 65800 and 65805 (paracentesis of anterior chamber of eye); 67141 (prophylaxis of retinal detachment); and, 68810 (nasolacrimal duct probe).
CMS also added to the ASC procedures list several ophthalmic surgical services that have recently received CPT codes, including 66711 (ciliary endoscopic ablation).
Though enthusiastic regarding CMS acceptance of many of its recommendations, OOSS attorney Michael Romansky said the organization remains unhappy that the agency continues to refuse to add to the ASC procedures list a number of ophthalmic surgical services which OOSS says can be safely and effectively furnished to Medicare beneficiaries in the ASC environment. These include: 65855 (trabeculoplasty); 67105 (retina repair, photocoagulation); 67145 (prophylaxis of retinal detachment, photocoagulation); 67210 (destruction of retinal lesions, photocoagulation); 67221 (destruction of retinal lesions, photodynamic therapy), and 67228 (destruction of extensive or progressive retinopathy, photocoagulation).
Romansky says OOSS will continue to seek enactment of legislation that will abolish the ASC procedures list and replace it instead with a list of those procedures which may not be clinically appropriate for the ASC environment.