Article Date: 10/1/2009

New Alcon Initiatives in Retinal Arena
SUBSPECIALTY NEWS

RVO Data Revealed at Retina Congress

Clarifying the roles of anti-VEGF and steroid therapy.

JACK PERSICO, EXECUTIVE EDITOR

■ New landmark trials of therapies for macular edema due to retinal vein occlusion, presented earlier this month at the Retina Congress in New York, represent the first significant rethinking of RVO clinical protocols to appear in the literature since Ronald Reagan's first term in office. In the 25 years since the BRVO Study Group's 1984 paper demonstrated a modest improvement in visual acuity from macular grid photocoagulation, better options have gone wanting, although off-label use of steroids and anti-VEGF agents have been used in recent years.

With the release of phase 3 data from the BRAVO, CRUISE and SCORE studies, retinal specialists now have hard data to guide treatment decisions that previously were conducted off label, and the newly-approved dexamethasone intravitreal steroid implant (Ozurdex) expands the options further.

David M. Brown, MD, of Houston presented the CRUISE study of central RVO patients, in which 392 subjects at 95 US sites were randomized to 0.3 mg ranibizumab, 0.5 mg ranibizumab or sham injection, administered monthly for six months. "While the sham arm had relatively little improvement from baseline to month six," said Dr. Brown from the podium, "the ranibizumab arms had a rapid and robust improvement, with the average patient gaining eight letters by day seven and improving to 12.7 letters in the 0.3 mg arm and 14.9 in the 0.5 mg arm at the sixmonth primary endpoint." Sham-treated patients improved by 0.8 letters at month six.

Over 20% of ranibizumab-treated patients gained greater than 15 letters of BCVA by day seven, Dr. Brown said, increasing to 46.2% and 47.7%, respectively, in the 0.3 mg and 0.5 mg groups at six months. "This compares to the slow improvement in the natural history sham arm," he explained, "where 16.9% had a three-line gain at month six." Subjects randomized to ranibizumab were about three times more likely to gain greater than 15 letters compared to the sham cohort, he summarized.


IMAGE COURTESY OF ALEXANDER BRUCKER, MD

Clinicians now have a wealth of new data on how to treat macular edema subsequent to RVO.

In the similarly-designed BRAVO study, 397 branch retinal vein occlusion patients at 93 US sites were randomized to 0.3 mg ranibizumab, 0.5 mg ranibizumab, or sham injection, administered monthly for six months. Those in the treatment arms gained 7.6 letters (0.3 mg group) and 7.4 letters (0.5 mg group) of BCVA at day seven after the first injection, followed by continual improvement throughout the study period, ultimately achieving BCVA gains of 16.6 letters in the 0.3 mg group and 18.3 letters in the 0.5 mg group at six months. Sham patients ended the study with a mean 7.3-letter gain. "This difference of 11 letters and 9.3 letters was statistically significant, as were all differences at all time points," presenter Peter Campochiaro, MD, said from the podium. Patients achieving gains of 15 or more letters represented 55.2% of the 0.3 mg group and 61.1% of the 0.5 mg group compared to 28.8% of sham patients.

Turning from anti-VEGF to steroid therapies for retinal vein occlusion, the attention-getting studies at Retina Congress elaborated on the impact of intravitreal triamcinolone and introduced the new dexamethasone implant.

The NEI Institute-funded SCORE study — two independent trials, one of CRVO that enrolled 271 patients and a second of BRVO with 411 subjects — compared 1 mg and 4 mg doses of intravitreal triamcinolone to "standard care," defined as observation in the CRVO trial and laser photocoagulation (when advisable) in the BRVO trial. Percent of subjects achieving BCVA improvement of 15 or more letters at 12 months was the primary outcome in each study. Patients were followed at four-month intervals for two years.

The CRVO trial found that 27% of 1 mg-treated patients and 26% of 4 mg-treated patients reached the primary outcome vs 7% in the observation group. Both triamcinolone groups were superior to the observation group in visual acuity at 12 months. "The visual benefit of triamcinolone was demonstrated as early as four months," said presenter Michael Ip, MD, "and continued out to 24 months."

Given that the 1 mg dose demonstrated a safety profile superior to the 4 mg dose and similar to that of the observation group, the authors concluded that the 1 mg triamcinolone dose, using the retreatment criteria in the SCORE study, should be considered in patients comparable to those enrolled for up to 12 months and possibly two years, Dr. Ip explained.

Unlike the CRVO data, the SCORE study's BRVO data, presented by Ingrid Scott, MD, favored standard care rather than intravitreal triamcinolone. The endpoint of 15 or more letters gained in BCVA at one year was achieved by 29% of standard care patients vs 26% of the 1 mg dose group and 27% of those in the 4 mg group.

"All three groups had a similar gain of approximately four to six letters in mean visual acuity letter score from baseline to month 12," Dr. Scott mentioned in her presentation. Beyond 12 months and through month 36, the mean change from baseline was greater in the standard-care group than either triamcinolone group. The safety profile of standard care was superior as well. The SCORE BRVO trial supports grid laser as the continued standard care treatment, given its comparable efficacy and improved safety, Dr. Scott said.

While the ranibizumab RVO data are slated for submission to the FDA in pursuit of a labeling change for Lucentis, Allergan's newly-introduced Ozurdex implant holds the distinction of being the first FDA-approved treatment for venous occlusive disease.

Unlike the CRUISE, BRAVO and SCORE studies, the Ozurdex trial pooled BRVO and CRVO cases into one data set, comprised of 1267 patients. Patients were randomized to the dexamethasone implant at a 0.7 mg or 0.35 mg dose, or a sham injection, implanted at baseline and followed for six months. At the six-month visit, they could receive a second implant if visual acuity was below 20/20 or central retinal thickness was above 250 μm.

Time to achieve a 15-letter gain in BCVA was the study's primary endpoint. At one month, results in the treated groups began to separate from the sham group. Visual improvement peaked at 60 days and tapered thereafter out to 180 days in all three groups, at which time a cumulative 41% of treated patients had gained three or more lines of vision, compared with 23% of sham patients. Looking at downside risk of VA loss of three lines or more, implantation of the 0.7 mg dexamethasone implant reduced risk of severe visual loss by about half.

"Interestingly, about 20% of patients overall required only one treatment" to maintain their favorable visual and central retinal thickness status out to the one-year endpoint of the study, said Julia Haller, MD, of Philadelphia's Wills Eye Hospital during her presentation of the data.

Patients receiving sham implant who went on to receive dexamethasone treatment at six months were unable to "catch up" to the outcomes achieved in those treated at baseline, Dr. Haller said, suggesting that delay of treatment did not improve long-term results.

Questions regarding potential combination regimens for RVO that involve concurrent use of Ozurdex and Lucentis will no doubt arise and form the basis of future studies.

Dr. Ambati: In the Forefront of AMD Research

He Sees Major Changes Coming in Treatment.

RENÉ LUTHE, SENIOR ASSOCIATE EDITOR

■ In the not-too-distant future of retinal disease management, Jayakrishna Ambati, MD, PhD, predicts the ascent of sustained-delivery drug devices over injectable drugs. "I think the era of just injecting people every month in their eye is coming to an end," he says. "We already have several of them (drugdelivery devices) now available or soon to be on the market."

Among Dr. Ambati's other predictions: In perhaps 10 years, molecularly targeted treatment of diseases will prove effective and some next-generation therapeutics will be personalized based on genetic information.

Dr. Ambati's position as professor of physiology and professor and vice chair of Ophthalmology and Visual Sciences at the University of Kentucky, as well as leader of the Ambati Lab at the university, gives him a special vantage point on the state of research in the field. He reports that his 22-member team has had an "amazing decade" since he joined the university in 2001. A breakthrough published in a recent issue of the journal Nature details his team's finding that could address the shortcomings of anti-VEGF therapy. For while VEGF targeting has been beneficial for improving vision in certain patients, Dr. Ambati notes that it also leaves a substantial number with severe vision loss.

"Much more can be done for the wet form of macular degeneration," Dr. Ambati says.

One answer, he thinks, may be a molecule called CCR3. His research team has found it to be the first molecular signature of macular degeneration in humans — "a molecule that's found only in the diseased state, present in the human choroidal neovascularization membranes, but not in other diseases and normal eyes" he says.

Targeting it, Dr. Ambati reports, has shown better outcomes, in experimental models, than targeting VEGF.

Jayakrishna Ambati, MD, PhD.

"Even more exciting, we found you could do something called quantum dot bio-imaging, which is to use quantum dots that target CCR-3, define these blood vessels even before they've invaded the retina," Dr. Ambati explains. "Theoretically, if we can do this in people, then we can actually detect the blood vessels before they disrupt vision; we've shown in experimental models that can be done."

Dr. Ambati has also established a reputation as being somewhat controversial after his warnings about the possible toxicity of 21-NT siRNAs. (Two of these siRNAs have failed in key clinical trials for wet AMD but their sponsors say the failures were not caused by side effects). And while Dr. Ambati sounds a note of caution about using 21-NT molecules to treat wet AMD, he says that his research team continues to work on siRNAs, which he calls "an amazing technology."

"We have two areas of interest: one is to see how we can make them more specific at targeting what they are designed to target. The other is to understand the importance of RNAs in macular degeneration as a whole. I think we'll get there, but it probably won't be as soon as we had imagined a decade ago."

It is contributions to leading-edge macular degeneration research that Dr. Ambati believes have helped him attract talented scientists to his research team. He feels that the team has done its most valuable work unraveling what he calls "unexpected intersections" between immunology, macular degeneration, and vascular biology.

"I think we have found some very important crossroads that tie the immune system with blood vessel growth and how that leads to macular degeneration. We also now see links between the immune system and geographic atrophy," Dr. Ambati says.

Despite the impressive breakthroughs in recent years, Dr. Ambati says significant challenges remain.

The biggest remaining challenge, he believes, is the disease itself. "It's amazing that something that happens in such a small region of the human body — a few cubic millimeters wide — can just confound the collective intelligence of so many bright people around the world. What is actually causing this disease?"

Charlesson Has Dual-Focus in Retina Research

It Funds its Drug Development With Contract Work.

LESLIE GOLDBERG, ASSOCIATE EDITOR

■ Charlesson LLC, an Oklahomabased early-stage drug-development company focused on treating retinal diseases, partially funds its drug development by serving as a contract research organization (CRO) for other drug companies. Charlesson was founded in 2003 by Michael Moradi, an entrepreneur who has founded or been a principal in several nanotech and pharmaceutical startups, and scientific co-founder Jian-Xing Ma, MD, PhD, an expert in the field of diabetes research. The pair recognized the need for new treatments in retinal diseases.

Charlesson researchers at work.

Charlesson's entry into specialty contract research happened by accident, says Mr. Moradi. "We had been developing a peptide-based drug for macular degeneration and tried to license it to a larger company. They had no interest in our drug, as it was too early in development, but they looked at the data and loved the model. They asked if we could provide this service for them and that's how we fell into the contract research business."

Mr. Moradi says the company has no outside investors, no debt and current annual revenues in the $2 million range. The company has been funded to date with more than $11 million in nondilutive capital from grants and CRO revenue. It does not advertise and has grown by word of mouth. "The real magic is that we have access to low-cost facilities and good animal models," says Mr. Moradi. "This is the fundamental advantage of our CRO."

A team of scientists performs preclinical research on a contract basis. In order to maintain independence, the company keeps CRO personnel separate from internal drug development work so that there is no real overlap.

Charlesson is primarily focused on retinal animal models. "We do some cell culture that is more generic in nature but we don't want to branch out from our core expertise, which is the eye," says Mr. Moradi. "This is a robust marketplace. The recession has done two things that have affected our company. While it is true that some clients have slowed down projects, the economy has also forced some groups to scale back their research divisions, requiring more outsourcing — driving business our way."

CLT-003, the drug furthest along in Charlesson's pipeline, is a sustained-release injectable whose primary indication is diabetic macular edema. Moradi says that the company's philosophy on retinal drug development is differentiation from most of the existing treatments, which are active against fighting wet AMD and treating VEGF.

Charlesson CEO Michael Moradi.

"We see an opportunity upstream in the disease cascade — where you are shutting off the new blood vessel growth at its source rather than treating VEGF further downstream," says Mr. Moradi. "At the moment there is no FDA-approved therapeutic for DME. Given there are no good therapeutic options, I believe we as an industry can do a better job."

Charlesson has been ranked by Inc. magazine as number 264 in the 28th annual Inc. 500, an exclusive ranking of the fastest-growing private companies nationwide. Charlesson was also identified as the 23rd fastestgrowing private company in the health category. For more information on the company, visit its Web site at www.charlessonllc.com.

IN BRIEF

24-month data on epimacular brachytherapy for AMD. Use of epimacular brachytherapy in conjunction with bevacizumab can reduce the number of intravitreal injections needed to maintain or improve vision, according to 24-month data presented at the Retina Congress of a phase 2 multicenter study that will continue to the three-year mark.

The study called for two bevacizumab injections to be given, one at or before administration of strontium 90 radiation and the second one month later. Retreatment was then based on the investigator's discretion.

At 24 months, 76% of subjects had received no additional injections; the mean number of injections was 2.4 (including the two at the outset).

A majority of patients maintained visual acuity and at least 20% also experienced a marked improvement in vision at month 24.

Applying current OCT-based guidelines on bevacizumab retreatment (unavailable at the time of study initiation) could potentially have increased the number of injections, but also the visual acuity outcomes.

OPKO has new ideas for bevasiranib. OPKO Health told a recent investor conference that it was considering new approaches for the development of bevasiranib, whose phase 3 clinical trial for wet AMD was terminated in March due to lack of efficacy. Bevasiranib was the first siRNA drug to advance to a US phase 3 study and as such had attracted interest from a wide spectrum of the pharmaceutical community.

Jamie Freedman, MD, PhD, OPKO executive vice president for R&D, reported in a Sept 22 presentation that the company may initiate new studies that could encompass more frequent dosing, combination dosing with Lucentis, or a novel drug-delivery system. Dr. Freedman said that the phase 3 trial had demonstrated some promising early data when bevasiranib injections were alternated with Lucentis injections.

OPKO acquired bevasiranib through the acquisition of the drug's developer, Acuity Pharmaceuticals, after a highly encouraging phase 2 trial conducted by Acuity.

"I think that it is a good idea to redesign the phase 3 trial utilizing an induction/maintenance approach with Lucentis," said Michael Tolentino, MD, the original co-developer of bevasiranib. "This may be able to minimize Lucentis injections and maximize the benefit of bevasiranib."

VEGF-Trap trials fully enrolled. Regeneron Pharmaceuticals has announced the completion of patient enrollment in two large, randomized, double-masked, phase 3 clinical trials evaluating VEGF Trap-Eye in the treatment of wet AMD.

In each study of the VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD) program, VEGF Trap-Eye is being evaluated for its effect on maintaining and improving vision when dosed as an intravitreal injection on a schedule of 0.5 mg every four weeks, 2.0 mg every four weeks, or 2.0 mg every eight weeks (following three monthly doses), as compared with intravitreal ranibizumab administered 0.5 mg every four weeks during the first year of the studies. PRN dosing with both agents is being evaluated during the second year of each study. These studies are part of the global development program for VEGF Trap-Eye being conducted by Regeneron and Bayer HealthCare AG. Each study has enrolled in excess of the targeted 1,200 patient goal. One-year primary endpoint data from both studies are expected in the fourth quarter of 2010.

New data on Iluvien. Alimera Sciences has released positive interim 18-month safety and efficacy results from the first human pharmacokinetic study (PK Study) of the intravitreal insert Iluvien. In this 36- month phase 2 trial, the insert is providing extended-release delivery of fluocinolone acetonide to treat DME.

A total of 37 subjects were enrolled in the PK Study, 20 on a low dose (0.23 μg per day), and 17 on a higher dose (0.45 μg per day).

In the interim readout, 55% of the high-dose patients had an improvement in BCVA of 10 letters or more and 36% gained 15 letters or more. Among low-dose patients, 23% had an improvement in BCVA of 10 letters or more while none showed an improvement in BCVA of 15 letters or greater at this time point.

No patients receiving the low dose experienced IOP increases of 30 mmHg or greater at any time point, while 29% of the patients receiving the high dose experienced IOP increases of 30mmHg or greater at some time point.

"Any comparison of visual acuity response between the doses is confounded by the significant differences in baseline mean visual acuity, as well as the small sample size, which is susceptible to single-patient variability. However, the trends continue to be consistent with our expectations that sub microgram levels of corticosteroids will benefit this population," said Ken Green, PhD, Alimera's chief scientific officer.

In related news, Alimera has begun enrollment for a pilot study of safety and efficacy of Iluvien in macular edema secondary to retinal vein occlusion. The randomized, doublemasked pilot study, named FAVOR (Fluocinolone Acetonide for Vein Occlusion in Retina), compares two doses of Iluvien (0.23 and 0.45 micrograms per day).

CE Mark for Vidion. The epimacular brachytherapy device developed by NeoVista will soon debut in Europe, now that the device has received the CE mark from regulators there. Vidion treats wet AMD by applying targeted doses of strontium 90 ionizing radiation, sparing the patient the side effects typical of external beam radiation and possibly cutting down on the number of anti-VEGF injections needed.

A new Amsler Grid? A Swedish neuro-ophthalmologist has developed an alternative to the Amsler grid, the tool developed by Swiss ophthalmologist Marc Amsler in the 1950s as a device for early detection of macular disease.

Citing a high incidence of negative results using the class Amsler grid, Lars Frisén, MD, PhD, of the University of Gothenburg, created a new version of the grid using computer technology, dubbed "MacuFlow." Although further assessment is needed, initial evaluations of simulated scotomata and metamorphopsia using the updated grid showed promising results. RP



Retinal Physician, Issue: October 2009