18.3% of CATT Patients Developed GA
Study implicates anti-VEGF therapy.
BY JERRY HELZNER, SENIOR EDITOR
■ One of the great unresolved questions to come out of the recent, large-scale CATT trial comparing the safety and efficacy of ranibizumab (Lucentis, Genentech, South San Francisco, CA) with bevacizumab (Genentech) was whether repeated dosing of these anti-VEGF therapies over a period of time could trigger geographic atrophy (GA) in patients who had shown no signs of GA at baseline.
A number of respected retina specialists, including Philip Rosenfeld, MD, PhD, of Bascom Palmer Eye Institute in Miami, FL, have been leaning toward the position that repeated anti-VEGF over time can trigger GA. However, Dr. Rosenfeld and others wanted to see additional studies that might provide confirmation of this hypothesis.
Now, a team of researchers led by Juan E. Grunwald, MD, of the University of Pennsylvania, has published a study of 1,024 CATT patients whose color fundus photos or fluorescein angiograms showed no visible signs of GA at enrollment. After two years, the researchers found that GA had developed in 187 patients, or 18.3% of the cohort being studied.
While the researchers noted several possible factors that could have contributed to the development of GA, including lower visual acuity at baseline, retinal angiomatous proliferation, and foveal intraretinal fluid, they also implicated monthly dosing and the use of ranibizumab in GA development. They concluded that “anti-VEGF therapy may have a role in the development of GA.”
“This study confirms the suspicions previously raised,” says Dr. Rosenfeld. “This new analysis is all very consistent with prior reports. The information I want to see is whether the appearance and growth of GA in the HARBOR study was influenced by monthly dosing or the higher Lucentis dose. These are very important data.”
Grunwald JE, Daniel E, Huang J, et al. Risk of geographic atrophy in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Ophthalmology. 2013 Sep 30. [Epub ahead of print]
■ FDA again fails to approve Iluvien For the third time, the FDA has denied approval for Alimera Sciences’ long-duration implant for the treatment of chronic DME.
The implant, designed by Alimera’s partner pSivida for the sustainedrelease dosing of the steroid fluocinolone acetonide for up to 36 months, was rejected because the FDA found the risk and safety issues continued to outweigh the benefits, according to the agency. Iluvien side effects can include cataract and glaucoma.
The FDA stated that it could not approve the new drug application in its present form. To address the clinical and statistical deficiencies the FDA identified, the agency indicated that results from a new clinical trial would need to be submitted, together with at least 12 months of follow-up for all enrolled patients.
The FDA suggested that a meeting with the Dermatologic and Ophthalmic Drugs Advisory Committee may aid in addressing the deficiencies it pointed out and in providing advice whether a patient population can be identified in which the benefits of the drug product might outweigh the risks.
“We will continue to work with the FDA, through the advisory committee, to determine whether there is a path forward in the United States for Iluvien,” says Dan Myers, president and CEO of Alimera. “We remain excited about Europe, however, where we have aligned our energy and resources to support the expansion of our business there. Our current traction in the countries in which Iluvien has already been approved, coupled with our continued pursuit of further country approvals, should position us well for future growth, irrespective of the US outcome.”
■ In the article “Management of Hazy View and Small Pupil During Vitreoretinal Surgery” (September 2013, pages 40-44), the manufacturers of two products were misidentified. Alcon (Fort Worth, TX) manufactures Viscoat, while Abbott Medical Optics (Santa Ana, CA) manufactures Healon 5. Retinal Physician regrets the error.
Genentech Not Resting on Lucentis Laurels
Company readying new initiatives in retina therapy.
BY JERRY HELZNER, SENIOR EDITOR
■ For those who have been waiting to hear how anti-VEGF pioneer Genentech (Roche, South San Francisco, CA) intends to counter the promising initiatives in combination retinal disease therapies brought forward by its rivals, your wait is over.
In a wide-ranging interview with Retinal Physician, Gary Sternberg, MD, therapeutic area head for ophthalmic medical affairs for Genentech, described a bispecific, single-molecule combination that the company believes is on schedule to move into a phase 1 clinical trial in 2014. As Dr. Sternberg describes it, the combination will contain an anti-VEGF element and another targeted therapeutic that could be an anti-PDGF agent or something else that the company may choose for the trial.
“This combination will not be coformulated and will be delivered with a single injection,” Dr. Sternberg says. “It will act in the eye with high potency but, upon entering the systemic circulation, be rapidly eliminated with low systemic exposure to the drug.”
Dr. Sternberg says the combination is based on “elegant technology” and is intended to improve efficacy, which may possibly decrease the number of injections and monitoring visits that a patient will require in the course of a year.
DELIVERY SYSTEMS EXPLORED
While Genentech is developing its combination drug, it is also actively exploring a number of novel concepts in drug delivery, including sustained- release formats. In this area, Genentech has been working with ForSightVision4 (Menlo Park, CA) and is looking at other delivery concepts that it believes have potential.
“For drug delivery, we are taking multiple shots on goal,” says Dr. Sternberg. “New methods of drug delivery are a high priority for us.”
Another priority for the company is developing personalized medicines that can be tailored to specific patients or subsets of patients.
“We have a strong commitment to developing the right drugs for the right patients, whether that is based on genetic markers or disease-specific factors,” Dr. Sternberg says. “In our recent phase 2 MAHALO trial for geographic atrophy [GA], we were able to identify a subset of patients with a specific biomarker whose progression rate was reduced by more than double the rate of the overall study population.”
On the question of whether heavy or prolonged dosing of anti-VEGF can trigger GA, Dr. Sternberg says Genentech believes the question warrants further study and is looking closely at the company’s HARBOR trial, which had monthly and asneeded arms with both a 2-mg and an 0.5-mg dose.
“We are studying all the HARBOR data, including the findings from fellow eyes, to determine whether there was GA and, if there was, whether this was underlying GA or if the GA might have been drug or regimen-induced.”
LOOKING AT THE FUTURE
Asked to predict how retinal disease would be treated 10 years from now, Dr. Sternberg says he believes the primary delivery system would still be intravitreal injections, which have been proven safe. However, he believes that with newly developed therapies, probably combinations or sustained delivery, patients would only need two or three injections a year and far fewer monitoring visits.
Adds Dr. Sternberg: “Genentech is exploring multiple research opportunities in the ophthalmic space and plans to play a significant role in the development of ophthalmic treatments for years to come.”
■ Genetic marker for RP identified. Researchers led by physicians at Bascom Palmer Eye Institute in Miami, FL, say they have recently produced a breakthrough discovery in diagnosing retinitis pigmentosa (RP) in the form of an easily identifiable genetic marker.
Rong Wen, MD, PhD, and Byron Lam, MD, professors of ophthalmology at Bascom Palmer, in collaboration with biochemist Ziqiang Guan, PhD, a research associate professor at Duke University Medical School, discovered a key marker in blood and urine that can identify people who carry genetic mutations responsible for RP. “A simple urine test can tell who has the RP-causing mutations,” says Dr. Wen. “Collecting urine is noninvasive and easy.”
Allegro’s Key Drug in Two New Trials
Integrin peptide therapy targets wet AMD and VMT.
BY JERRY HELZNER, SENIOR EDITOR
■ Moving ahead on two fronts, Allegro Ophthalmics (San Juan Capistrano, CA) has advanced its integrin peptide inhibitor ALG-1001 into two new phase 2 clinical trials, one targeting wet AMD and the other symptomatic vitreomacular traction (VMT). The two studies were announced after the FDA approved Allegro’s Investigational New Drug application.
ALG-1001 is unique in that it primarily targets the mechanism in the eye that produces VEGF rather than just targeting the VEGF itself. In disrupting VEGF production at its source, Allegro believes that ALG-1001 can achieve a more durable response, with visual improvement lasting up to six months. ALG-1001 monotherapy has demonstrated this capability in previous phase 1 trials for wet AMD and DME. In addition, Allegro believes that ALG-1001 could be used in combination with anti-VEGF agents to produce even better results and has initiated one such phase 1b/2a trial for the treatment of DME
ALG-1001 has also shown promise in the resolution of VMT in a phase 1 trial of end-stage DME patients.
“There were 15 subjects in the study, all receiving three monthly injections of ALG-1001 as monotherapy and then followed for three months off-treatment,” says Marc Kirshbaum, Allegro COO. “There was a 90-day washout period for either anti-VEGF or laser therapy. Of the 15 subjects enrolled in the study, 11 patients did not have a total PVD [posterior vitreous detachment] at baseline. Of these 11 patients, six developed a total PVD during the study, equaling 55%. These were all end-stage DME subjects for whom obtaining such a release is notoriously difficult.”
Replicating these results in larger, later-stage clinical trials would make ALG-1001 a competitor to Jetrea (ThromboGenics, Iselin, NJ), the only currently approved pharmacologic treatment for symptomatic VMT.
“We are extremely pleased with the FDA approval [of the new clinical trials], which validates our preclinical data, multiple phase 1 study results, and phase 2 clinical study design,” says Vicken Karageozian, MD, cofounder and chief technical officer of Allegro. “We’ve rapidly and methodically gone from compound discovery to phase 2 clinical trials. We are optimistic that this drug will continue to show efficacy and provide meaningful therapeutic benefit to patients with vascular eye diseases, such as wet AMD and VMT.”
■ Navilas laser plus anti-VEGF for DME. A 66-patient study led by Marcus Kernt, MD, of Ludwig Maximillians University in Munich, Germany, and presented at Euretina 2013, found that a combination of ranibizumab (Lucentis) and a single treatment with the Navilas Navigated Laser (OD-OS, Tetlow, Germany) for DME significantly reduced the need for ranibizumab retreatment compared to ranibizumab monotherapy.
At 12 months, following three initial loading doses of ranibizumab at the beginning of the study, Dr. Kernt found that 65% of the 34-patient combination group had required no further injections of ranibizumab, while 84% of the 32-patient monotherapy group had required retreatment to maintain vision gains. Both groups were seen monthly to determine the need for PRN retreatment.
■ Vision aid for RP patients gets CE mark. Retina Implant AG, a developer of subretinal implants for patients blinded by retinitis pigmentosa (RP), said its wireless subretinal implant technology, the Alpha IMS, has received the CE Mark. Retina Implant’s technology, which has been in clinical trials across the world since 2005, is designed to restore useful vision in patients with RP. To date, 36 patients have received the Alpha IMS microchip.
■ Jetrea is nominated for major biotech prize. Jetrea (ocriplasmin, ThromboGenics) has been nominated for the 2013 Prix Galien USA Award in the Best Biotechnology Product category. The Prix Galien USA is an international award that recognizes outstanding achievements in improving human health through the development of innovative therapies.
A nine-member committee from biotechnology and academia, including five Nobel laureates, will chose the winners.
Jetrea is the first and only FDA-approved pharmacological therapy for the treatment of symptomatic vitreomacular adhesion (VMA). RP