SUBSPECIALTY NEWS
Ophthotech’s Fovista Combats Subretinal Fibrosis
Combination therapy proves effective in clinical trial.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ In an independent subgroup analysis of 70 patients in a phase 2b trial, Ophthotech (New York, NY) reported that a combination of its Fovista anti-PDGF molecule and Lucentis was more effective than Lucentis monotherapy in stopping the development and progression of subretinal fibrosis.
On a severity scale of 0 to 4, with 0 the least severe, the mean change in severity of subretinal fibrosis from baseline to the conclusion of the study at 24 weeks was 0.97 vs 2.0 (P=.003), favoring the Fovista combination therapy group. At 24 weeks, approximately twice the number of patients on standard of care anti-VEGF monotherapy (54%) were noted to have progression of subretinal fibrosis compared to the Fovista combination group (27%). In eyes without any subretinal fibrosis at baseline, subretinal fibrosis developed in 10% of patients receiving Fovista combination therapy compared to 51% in the monotherapy Lucentis group.
In related news, Ophthotech Corporation has achieved a $50 million enrollment milestone payment from Novartis Pharma AG as part of the ex-US licensing and commercialization agreement between the two companies focused on the treatment of wet AMD. This enrollment milestone payment was triggered as a result of Ophthotech reaching the first enrollment goal under the agreement in its pivotal, multinational Fovista phase 3 clinical program and is the first of a total of $130 million in potential enrollment-based milestones under the agreement.
Under the agreement signed in May 2014, Ophthotech granted Novartis exclusive rights to commercialize Fovista in markets outside the United States, with Ophthotech retaining sole rights to commercialize Fovista in the United States. Potential payments to Ophthotech under the agreement could total over $1 billion in upfront and milestone payments, not including future royalties on ex-US Fovista sales.
IN BRIEF
■ Genentech to begin phase 3 trials for GA drug. Genentech (South San Francisco, CA) has announced the design of two large-scale phase 3, worldwide studies for lampalizumab, an investigational drug for geographic atrophy (GA) that showed promise in its phase 2 MAHALO study.
The phase 3 study program will evaluate the safety and efficacy of lampalizumab and its potential to slow the progression of GA. The studies will also further explore if people with a specific genetic biomarker, a mutation in complement factor I, may benefit more from lampalizumab treatment. No approved treatment exists for GA.
The MAHALO phase 2 primary endpoint showed a 20% reduction in GA lesion progression in patients treated monthly with lampalizumab as compared with sham at month 18. Additionally, data from a subpopulation of GA patients receiving monthly lampalizumab who were positive for the complement factor I (CFI) biomarker, demonstrated a 44% decrease in the rate of disease progression at 18 months. This exploratory biomarker analysis will be further evaluated in the phase 3 study.
The phase 3 trials, called CHROMA and SPECTRI, are identically designed, double-masked, randomized studies comparing a 10-mg dose of lampalizumab administered every 4 or 6 weeks by intravitreal injection to sham injections. Approximately 936 patients will be enrolled in each study.
■ Eylea receives “Breakthrough” designation for DME. The FDA has granted Regeneron’s Eylea (aflibercept) its “Breakthrough Therapy” designation for the treatment of DME. The drug was recently approved by the FDA for the DME indication.
The Breakthrough Therapy designation was created by the FDA to expedite the development and review of drugs for serious or life-threatening conditions. Drugs qualifying for this designation must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy. The designation includes all of the fast-track program features, as well as more intensive FDA guidance and discussion. The Breakthrough Therapy designation is distinct from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met.
Early Treatment of DME Limits Need for Anti-VEGF
Some patients go a year or more without retreatment.
■ Twenty-five percent of the 500 patients who elected to participate in an Open Label Extension study that followed Genentech’s RIDE and RISE trials for Lucentis (ranibizumab) required no further PRN treatment for DME in a follow-up period that ran an average of 14 months, and more than 2 years in some patients.
The follow-up study, led by Carl Regillo, MD, of Wills Eye Hospital, in cooperation with Genentech (South San Francisco, CA), concludes that early diagnosis, prompt treatment, less advanced disease and positive overall response during the 36-month RISE and RIDE studies were the keys to a reduced need for ongoing retreatment. The study was presented at the recent Retina Society meeting in Philadelphia.
While the study found that the mean number of PRN retreatments per patient in the extension study was 3.8 per year, or less than one retreatment every three months, the 25% who needed no PRN retreatment was a key finding.
In answering the question “Who Are the 25%,” Dr. Regillo described a profile of patients who had shorter duration of diabetes (by approximately 2 years) and diabetic macular edema (by approximately 8 months) compared to patients requiring frequent retreatment. These patients also tended to enter the RISE and RIDE studies with better BCVA and with thinner central foveal thickness (CFT). Overall, these patients experienced the most meaningful improvement during the RISE and RIDE studies and entered the extension study with thinner CFT than the patients who needed a large number (seven or more) PRN retreatments during the average 14.1 month follow-up period.
“For the 25% of patients in RISE and RIDE who did not require any injections during the PRN extension phase, therapy appears to have been initiated early, with shorter duration disease, higher visual acuity, less advanced DR, and less macular edema at baseline,” Dr. Regillo concluded. “With early diagnosis and treatment, a meaningful proportion of patients with DME may be able to stabilize disease and maintain vision gains without the need for ongoing intravitreal injections.”
IN BRIEF
■ Iluvien approved in the United States. The FDA has approved Alimera Science’s (Alpharetta, GA) Iluvien, the fluocinolone acetonide intravitreal implant, for the treatment of diabetic macular edema in patients who have previously been treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure, according to the company.
The sustained-release implant is injected into the back of the eye with an applicator that uses a 25-gauge needle. The implant has received approval in a number of EU nations. The FDA previously withheld approval, citing safety concerns. Iluvien is the first long-term treatment approved for DME.
■ Patient selection key to success with Jetrea. Alcon (Fort Worth, TX), which owns the international rights to Jetrea (ocriplasmin), the only FDA-approved medical treatment for vitreomacular traction, says new clinical studies of the drug continue to show that selection of appropriate patients is key to achieving success with Jetrea. Alcon presented four abstracts during sessions at the recent Euretina congress in London, each of which described real-world use of the drug in clinical practice.
Among the data the company highlighted were two studies focused on the importance of appropriate patient selection with Jetrea. Additional data demonstrated a safety profile consistent with that reported in the phase 3 clinical trials.
ThromboGenics (Iselin, NJ), which developed Jetrea, received FDA approval for the drug in 2012 and owns the US rights to the drug. Jetrea is delivered via a single injection into the eye.
■ Beaver-Visitec acquires Endo Optiks. Beaver-Visitec International (Waltham, MA) has acquired Endo Optiks (Little Silver, NJ), a developer and manufacturer of endoscopic instruments and equipment for ophthalmic procedures. Terms of the transaction were not disclosed.
Though Endo Optiks is best known for its endoscopic instruments used for performing endoscopic cyclophotocoagulation, the company’s endoscopes are also used for retinal procedures such as endoscopic vitrectomy.
Seven Researchers Share Prestigious Award
They pioneered the development of antiangiogenic therapy.
■ The one-million euro Antonio Champalimaud Vision Award for 2014 will be shared by seven researchers — sometimes working independently and sometimes in groups — who over two decades led in developing antiangiogenic therapy as a successful treatment for retinal diseases. Their discoveries led to the successful use of anti-VEGF drugs that have restored sight to millions of patients around the world with retinal disease.
The researchers, who received their awards at a ceremony in Lisbon, Portugal, in September, include Joan Whitten Miller, MD, Evangelos S. Gragoudas, MD, and Patricia A. D’Amore, PhD, MBA, of Massachusetts Eye and Ear; Lloyd Paul Aiello, MD, PhD., of Mass. Eye and Ear and Joslin Diabetes Center; George L. King, MD, of Joslin Diabetes Center; Anthony P. Adamis, MD, global head of ophthalmology, immunology and infectious diseases for Genentech, who is also affiliated with HMS Ophthalmology and Mass. Eye and Ear, and Napoleone Ferrara, MD, of the University of California, San Diego School of Medicine and formerly a Genentech scientist.
Champalimaud Award recipients are selected by a distinguished international panel that includes two Nobel Laureates. The award is often referred to as the “Nobel Prize for Vision” and with its one-million ($1.3 million) purse, it is among the world’s largest scientific and humanitarian prizes.
Beginning in the 1990s, the seven researchers worked either independently or in collaboration to identify VEGF as the major cause of such common retinal diseases as wet AMD, DME, diabetic retinopathy, and retinal vein occlusion. The researchers then demonstrated that blocking VEGF with regular intravitreal injections of anti-VEGF agents could eliminate or reduce the unwanted blood vessels that led to vision loss. The researchers’ groundbreaking work led to a new class of ophthalmic anti-VEGF drugs, which first became available in the United States in 2004. These drugs include Macugen (pegaptanib sodium, Eyetech), Lucentis, and Eylea (aflibercept, Regeneron Pharmaceuticals). RP
![](https://res.cloudinary.com/broadcastmed/image/fetch/q_auto,f_auto/dpr_auto/https://retinalphysician.com/media/lzjgv4ij/rp_oct_1201.jpg)
Anthony P. Adamis, MD, (left) and Napoleone Ferrara, MD (right)
IN BRIEF
■ Revised indication for Ozurdex. The US Food and Drug Administration has expanded the approval for dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan, Irvine, CA), the sustained-release biodegradable steroid implant, for the treatment of diabetic macular edema. The drug was first approved in June as a treatment for DME in adult patients who have an artificial lens implant or who are scheduled for cataract surgery. Based on ongoing review of clinical data, the FDA has approved Ozurdex for use in the general DME patient population.
In other news, the European Commission has extended the Marketing Authorization for Ozurdex to treat adult patients with visual impairment due to DME who are pseudophakic or who are considered insufficiently responsive to or unsuitable for noncorticosteroid therapy. The approval is based on the MEAD study. MEAD includes two multicenter three-year sham-controlled, masked, randomized studies assessing the proportion of patients with ≥15 letters improvement in baseline BCVA. The most common adverse events in the studies included cataracts and elevated IOP.
Corrections & Clarifications
■ In the September 2014 issue, the article “Maximize Efficiency in Your ASC,” page 38, should have included the disclosure that author Pravin U. Dugel, MD has a financial interest in Alcon. He is a consultant.
■ In the September “Coding Q&A,” column, page 12, Table 1, the correct CPT code for Ozurdex is 67028.
■ In September, the article “Pneumatic Retinopexy: Failure, 360º Laser, Pseuophakes” on page 42, in which Dr. Tornambe addresses his single-operation success (SOS) rate, the quote should state, “My current SOS is about 75%, so to increase my SOS by 10%, I would need to unnecessarily perform 360º laser on that 75% who would have had success without it. That seems excessive to me.”
Retinal Physician apologizes for the errors.
AREDS Formulations Increase AMD Risk for Some
People with certain genotypes should not take them.
■ DNA samples from 989 individuals who participated in the Age-Related Eye Disease Study (AREDS) indicate that people with a specific genotype should not be taking the AREDS formulation because it increases their risk of progression to the advanced form of AMD. The findings were recently presented in the September issue of Ophthalmology.
Carl Awh, MD, of Tennessee Retina Physicians, and colleagues evaluated DNA samples that had been collected from the AREDS trial. Overall, the AREDS trial showed a modest overall benefit of nutritional supplements for patients with AMD and became the model for most over-the-counter ocular supplement formulations. In this new study, the researchers analyzed four groups of patients, classified by their complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genetic risk.
The analysis found that for patients with high CFH and low ARMS2 risk, or 13% of the study participants, the risk of progression to advanced AMD within seven years was 43.2% for those treated with zinc, 40.2% for those treated with the AREDS supplement, and 17% for those receiving placebo.
“Patients in this genotype group had worse outcomes when treated with zinc or the AREDS formulation than with placebo,” asserted Dr. Awh. “AMD patients with two high-risk CFH alleles and no ARMS2 risk alleles — 13.1% of patients in our study — should not take the AREDS formulation.”
Dr. Awh contrasted this group against patients with low CFH and high ARMS2 risk, a group that made up 35% of study participants. For this larger group, the risk of progression to AMD within seven years was 37% lower for those taking the AREDS supplement than for those in this group who took the placebo.
“The AREDS supplements are quite helpful for patients in this group, which is the largest of the four genotype groups,” said Dr. Awh. “We think that the beneficial response of this genotype group, balanced by the poor response of patients with high CFH and no ARMS2 risk, are the basis for the overall modest benefit demonstrated in AREDS. Our analysis supports the use of genetic testing for patients before recommending an AREDS-type supplement.” RP
IN BRIEF
■ Avalanche sells shares; raises $106 million. Avalanche Biotechnologies, a developer of gene replacement therapies, has raised $106 million in new funding through the sale of 6 million shares of common stock to the public. The stock now trades on NASDAQ under the symbol AAVL.
Avalanche recently made news when it entered into a broadly based collaboration with Regeneron, the developer of Eylea, to discover, develop, and commercialize novel gene therapy products for the treatment of eye diseases. The partnership may signal that Regeneron now views a range of retinal diseases as potentially curable rather than chronic.
“We feel that the eye is one of the most attractive places to do gene therapy,” said George Yancopoulos, MD, PhD, Regeneron’s chief scientific officer. “The advantages include the ability to apply the therapy locally, deliver the gene therapy to the specific cells of interest, and directly observe its effect. Ultimately, the goal would be to have long-lasting effects or even cures.”
The new collaboration covers novel gene therapy vectors and proprietary molecules, discovered jointly by Avalanche and Regeneron and developed using the Avalanche Ocular BioFactor, an adeno-associated virus-based, proprietary, next-generation platform for the discovery and development of gene therapy vectors.
Avalanche has advanced its AVA-101 gene replacement treatment into a 40-patient phase 2a trial for wet AMD following a phase 1 study that demonstrated safety and efficacy. Data from the phase 2a trial is expected next year.
■ Kala begins two clinical trials. Kala Pharmaceuticals, a developer of nanotechnology-based products leveraging the company’s proprietary mucus penetrating particle (MPP) platform, has begun a phase 2 clinical trial to evaluate KP-121, the company’s loteprednol etabonate (LE)-MPP drug in patients with intraretinal or subretinal fluid secondary to RVO or DME. Kala has also initiated a phase 2 clinical trial of the LE-MPP in subjects with meibomian gland disease. In both trials, LE-MPP is being topically administered QID.