Subspecialty News

New dry AMD research; Iluvien three-year data; uveitis guidelines, advanced AMD and brain hemorrhage risk


Major Breakthrough in Dry AMD?

Dr. Ambati's team targets toxic RNA.

■ A team of researchers, led by University of Kentucky ophthalmologist Jayakrishna Ambati, MD, PhD, has discovered a molecular mechanism implicated in geographic atrophy. Concurrent with this discovery, Dr. Ambati's laboratory has developed two promising therapies for the prevention of this currently untreatable condition. This study also elaborates, for the first time, a disease-causing role for a large section of the human genome once regarded as non-coding “junk DNA.”

Their article, “DICER1 Deficit Induces Alu RNA Toxicity in Age-Related Macular Degeneration,” was published online by the journal Nature in February.

Dr. Ambati's team discovered that an accumulation of a toxic type of RNA, called Alu RNA, causes retinal cells to die in patients with geographic atrophy. In a healthy eye, a “Dicer” enzyme degrades the Alu RNA particles.

“We discovered that in patients with geographic atrophy, there is a dramatic reduction of the Dicer enzyme in the retina,” said Dr. Ambati, professor and vice chair of the department of ophthalmology and visual sciences at the UK College of Medicine. “When the levels of Dicer decline, the control system is short-circuited and too much Alu RNA accumulates. This leads to death of the retina.”

Alu elements make up a surprisingly large portion — about 11% by weight — of the human genome, comprising more than one million sequences. However, their function has been unknown, so they have been called “junk” DNA or part of the “dark” genome. The discovery of Alu's toxicity and its control by Dicer should prove of great interest to other researchers in the biological sciences, Dr. Ambati says.

Dr. Ambati's team developed two potential therapies aimed at preventing geographic atrophy and demonstrated the efficacy of both approaches using laboratory models.

The first model involves increasing Dicer levels in the retina by “over-expressing” the enzyme. The second involves blocking Alu RNA using an “anti-sense” drug that binds and degrades this toxic substance. UK has filed patent applications for both technologies, and Dr. Ambati's group is preparing to start clinical trials by the end of this year.

Response from the scientific community has been enthusiastic.

“These findings provide important new clues on the biological basis of geographic atrophy and may provide avenues for intervention through preventing toxic accumulation of abnormal RNA products,” said Paul Sieving, MD, PhD, director of the National Eye Institute.

“Ambati's latest research provides important mechanistic insights in geographic atrophy, and identification of this novel pathway may result in new therapeutic targets for a major cause of blindness,” said Napoleone Ferrara, PhD, a member of the National Academy of Sciences and Lasker-DeBakey awardee who is a researcher at Genentech.

This work has “widespread implications” for future study, said Stephen J. Ryan, MD, president of the Doheny Eye Institute and member of the Institute of Medicine. “The authors have opened an important line of research with real possibilities for future therapeutic intervention for patients with geographic atrophy.”

Dr. Ambati's laboratory is supported by the National Eye Institute.

Iluvien Three-year Trial Data Released

Does approval hinge on side-effect profile?

■ Alimera Sciences, Inc., a biopharmaceutical company that specializes in the research, development and commercialization of prescription ophthalmic pharmaceuticals, has reported positive results through month 36 of the completed FAME Study. The study was designed to measure the safety and effectiveness of Alimera's Iluvien implant as a long-term, sustained-release treatment for DME.

The FDA said in December that it would require the full 36-month trial results before it could make a decision on approving Iluvien. However, the FDA has since suggested that efficacy will be judged on previously announced 24-month results. Thus, the agency may have delayed approval largely to gain additional information on the drug's side-effect profile, specifically the incidence of cataract formation and IOP-lowering surgeries.

Patients in two separate 36-month phase 3 trials were randomized to receive either high-dose Iluvien, low-dose Iluvien or a control treatment. The primary endpoint for efficacy in the trials was the difference in the percentage of patients whose BCVA improved by 15 or more letters from baseline on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart at month 24 between the treatment and control groups.

Alimera previously presented data for both the low- and high-dose patient results at month 24. Based on these data, the company submitted a New Drug Application (NDA) last June for approval of only the low dose. Therefore, only the low-dose data is presented and discussed in this release. In December, the FDA failed do approve Iluvien, instead requesting a third year of clinical data and additional information on manufacturing specifics. No new clinical trials were requested.

Data through month 36 for the Full Analysis Set in Trial A demonstrated statistically significant therapeutic effects of 28.9% at month 30 and 28.4% at month 33 of Iluvien patients gaining 15 or more letters, compared to the control group, in which fewer than 17% of patients gained 15 or more letters. The therapeutic effect was maintained at month 36 (28.4% of patients gained 15 or more letters) while 18.9% of the control group gained 15 or more letters.

Results from Trial B were similar. Statistically significant therapeutic effects of 33.9% at month 30 and 29.6% at month 33 of Iluvien patients gaining 15 or more letters over baseline were demonstrated, and an effect of 29.0% was seen at month 36 compared to the control group, which had fewer than 18% of patients making such gains. At month 36, 29.0% of Iluvien patients gained 15 or more letters compared with 18.9% of control patients.

By comparison, at month 24 in Trial A, 26.8% of Iluvien patients and 14.7% of control patients had gained 15 or more letters. In Trial B, 30.6% of Iluvien patients and 17.8% of control patients gained 15 letters or greater over baseline.

As previously reported, Trial A and B data combined demonstrated a statistically significant effect at week three. This effect was maintained throughout the 36 months, with 28.7% of Iluvien patients and 16.2% of control patients having an improvement in BCVA of 15 letters or greater over baseline at month 24, 31.4% versus 15.1% at month 30, 29% versus 17.3% at month 33, and 28.7% versus 18.9% at month 36.

“This consistent response rate at month 24 and month 36, with a peak rate of 31.4% in month 30, is encouraging, and we believe demonstrates that Iluvien can provide a long-term option for the treatment of DME for up to three years,” said Dan Myers, president and CEO of Alimera Sciences.

The Full Analysis Set includes 376 patients in the Iluvien arm and 185 patients in the control arm, with 190 patients in Trial A and 186 patients in Trial B randomized to the Iluvien arm.

Safety was assessed for all patients treated with Iluvien in the study. IOP increases to 30 mm Hg or greater at any time point had been seen in 18.4% of the patients by month 36 compared to 16.3% by the month 24 readout. By month 36, 4.8% of patients had undergone an incisional surgical procedure to reduce elevated pressure versus 3.7% of patients by month 24. The incidence of cataract among patients with a natural lens in their eye at the start of the trial was 81.7% at month 36, with 80% undergoing a cataract operation, compared to 80% and 74.9%, respectively, at the time of the month 24 readout.

“We believe the statistical significance observed in both trials at month 33 meets the criteria for replication of efficacy in the two studies,” said Susan Caballa, senior vice president of regulatory affairs at Alimera. “We will provide this safety and efficacy data to the FDA so that it will have the opportunity to review it as part of our pending NDA for Iluvien for the treatment of DME.”

Uveitis Treatment Guidelines Often Not Followed

Study reveals much confusion among ophthalmologists.

By René Luthe, Senior Associate Editor

■ A survey of ophthalmologists and rheumatologists found that 75% either did not know or did not follow the guidelines for treating noninfectious uveitis.

According to the study, published in the January issue of Ophthalmology, guidelines recommend tapering the corticosteroids (CS) used to treat non-infectious uveitis to 10 mg or less per day within three months. Significant adverse effects, including weight gain, hypertension, cardiovascular events, development of glaucoma, cataract and diabetes, are associated with chronic use of systemic corticosteroids, with steroid-sparing agents recommended if control of uveitis cannot be achieved by ≤ 10 mg/day of prednisone, or equivalent, within that time period.

Researchers, however, found wide divergence from these recommendations. The cross-sectional, multi-site study included 60 ophthalmologists and three rheumatologists; of the ophthalmologists, 37 had specialty training (retina: 19; uveitis: 11; cornea: 4; others: 3). Data was gathered with a study-specific questionnaire and physicians were questioned about their awareness and/or use of the recommended treatment guidelines. Patients with uveitis who required systematic CS treatment comprised approximately 5% of each physician's practice, with a total of 580 such patients randomly selected for analysis in the study. A minimum quota of 30 to 35 patients was established for each type of noninfectious uveitis — anterior, intermediate, posterior and panuveitis. Fifty-eight percent of the patients were female, and mean and median age of patients was 45 years.

For treatment, 360 of the 580 patients (62%) received systemic corticosteroids. Systemic therapies were prescribed in 100% of anterior uveitis cases, 57% intermediate uveitis cases, 84% of posterior uveitis cases and 86% of panuveitis cases. The mean oral CS dose at initial diagnosis ranged between 35 mg/day in the intermediate uveitis group and 60 mg/day in the posterior uveitis group. At current/most recent visit, mean dosage ranged from 36 mg/day in the anterior and posterior uveitis groups to 42 mg/day in the panuveitis group. The mean duration of systemic CS therapy was 21 months.

“The findings underscore the need to place further emphasis on educating the medical community and reinforcing treatment guidelines to improve the care of patients with uveitis,” the authors concluded.

Advanced AMD Linked to Brain Hemorrhage

■ Older people with late-stage AMD appear to be at an increased risk of intracranial hemorrhage (bleeding stroke), but not stroke caused by infarction (blood clot), according to research presented at the American Stroke Association's International Stroke Conference 2011.

“Other studies have found there are more strokes in older individuals with late AMD, but ours is the first to look at the specific types of strokes,” said Renske G. Wieberdink, MD, study researcher and epidemiologist at Erasmus Medical Center in Rotterdam, the Netherlands. “We found the association is with brain hemorrhage, but not brain infarction.”

Because the number of brain hemorrhages observed in the study was small, the findings will need to be corroborated in a larger group, Dr. Wieberdink said. “These findings should be considered preliminary,” she said. “Patients and physicians must be very careful not to over-interpret them. We don't know why there are more brain hemorrhages in these patients or what the relationship with AMD might be. This does not mean that all patients with late-stage AMD will develop brain hemorrhage.”

Begun in 1990, the Rotterdam Study is a prospective, population-based cohort investigation into factors that determine the occurrence of cardiovascular, neurological, ophthalmological, endocrinological and psychiatric diseases in older people. The researchers tallied stroke incidence among 6,207 participants 55 years and older. All of the participants were stroke-free at the study's outset. AMD was assessed during scheduled eye examinations, and participants with the condition were divided into five different stages of AMD, and whether their condition was wet AMD or dry AMD.

Participants were tracked for an average of 13 years. Of the 726 persons who suffered a stroke in that time, 397 were brain infarctions, 59 were brain hemorrhages and the stroke type was not available for 270. Late AMD (stage 4) was associated with a 56% increased risk of any type of stroke. Late AMD, both the dry and the wet form, was strongly associated with more than six times the risk of brain hemorrhage, but not with brain infarction. Early AMD (stages 1-3) did not increase the risk of any stroke. Associations were adjusted for possible confounders, such as diabetes, blood pressure, anti-hypertensive medications, smoking status, body mass index, alcohol use and C-reactive protein levels.

“We cannot yet say if there is a common causal pathway or mechanism of action — this association needs to be further investigated,” Dr. Wieberdink said. “But I don't think it is a causal relationship. It seems more likely that late AMD and brain hemorrhage both result from some as yet unknown common mechanism.”

If the findings are replicated, it may be possible to develop some stratification of risk among such patients, Dr. Wieberdink said.

Regeneron/Bayer begin Asian VEGF Trap-Eye trial in pathologic myopia. Regeneron and Bayer HealthCare have announced initiation of a new phase 3 clinical trial in collaboration with the Singapore Eye Research Institute investigating the efficacy and safety of VEGF Trap-Eye in patients with choroidal neovascularisation of the retina as a result of pathologic myopia. The trial has started in Japan and other Asian countries, including China, Korea, Singapore and Taiwan.
Myopia is highly prevalent in Asian populations, including Singapore, where 40% of adults have myopia and nearly 10% have high myopia. Currently, there is no well-established treatment for myopic CNV. VEGF Trap-Eye has previously met its primary efficacy endpoint in a phase 3 trial for wet AMD.
VEGF Trap submitted for FDA approval. Regeneron Pharmaceuticals has submitted a Biologics License Application (BLA) to the FDA for VEGF Trap-Eye for the treatment of wet AMD. Regeneron requested a Priority Review, which, if granted, would shorten the FDA's targeted goal for review time to six months.
“There have been significant advances in the treatment of wet AMD in recent years. However, the need for monthly intravitreal injections to obtain optimal vision gains has resulted in a significant burden for physicians, patients and their caregivers,” said Leonard S. Schleifer, MD, PhD, president and CEO of Regeneron. “We have conducted the largest global phase 3 clinical program in patients with wet AMD, which demonstrated that patients treated with VEGF Trap-Eye 2 mg every two months, following three loading doses, were able to be dosed with fewer injections over one year without compromising efficacy.”
The VEGF Trap-Eye BLA is based on the positive results from two phase 3 trials, the North American VIEW 1 trial and the global VIEW 2 trial. In these trials, all regimens of VEGF Trap-Eye, including VEGF Trap-Eye dosed 2 mg every two months, successfully met the primary endpoint of non-inferiority, compared to the current standard of care, ranibizumab 0.5 mg dosed monthly.
Lucentis DME trial meets endpoint. Genentech said that one of two phase 3 studies evaluating monthly Lucentis injections in patients with DME met its primary endpoint. The study, known as RISE, showed that a significantly higher percentage of patients receiving monthly Lucentis achieved an improvement in BCVA of at least 15 letters on the eye-chart at 24 months, compared to those in a control group, who received a placebo injection.
RISE is a multicenter, randomized, double-masked, 36-month study designed to assess the safety and efficacy profile of Lucentis in 377 patients with DME. The primary endpoint compared the proportion of Lucentis and sham-treated patients who gained at least 15 letters in BCVA at month 24 compared to their BCVA at baseline.
Patients were randomized to receive monthly injections of either 0.3 mg Lucentis (n=125), 0.5 mg Lucentis (n=125), or monthly sham injections (n=127). The study was not designed to compare the two doses of Lucentis, but each dose against the control group.
The second Lucentis DME study is an identical, parallel, confirmatory trial called RIDE but no results from that study have yet been released.
Orphan drug status for LCA therapy. QLT Inc. said the FDA has granted orphan drug designation for QLT091001, its oral synthetic retinoid, for the treatment of Leber Congenital Amaurosis (LCA). QLT091001 is a replacement for 11-cis-retinal, a key biochemical component of the visual retinoid cycle.
“We are pleased to have received FDA orphan drug designation for QLT091001 as a potential treatment for LCA, as there are no FDA-approved treatments for children suffering from this debilitating disease,” said Bob Butchofsky, president and CEO of QLT. RP