Article Date: 7/1/2010

Small Study Jumps the Gun on CATT
SUBSPECIALTY NEWS

Small Study Jumps the Gun on CATT

■ While the retina community eagerly awaits data from the larges cale CATT trial directly comparing Avastin and Lucentis in wet AMD, a group of researchers from the VA Boston Healthcare System has conducted a similar head-to-head studyon a much smaller scale.

In data presented at the recent ARVO meeting, 11 patients receiving Avastin and seven patients receiving Lucentis were evaluated for one year. All patients received three initial monthly doses, followed by an OCT-guided variable dosing regimen. Main outcome measures were visual acuity and foveal thickness at one year.

The average preoperative visual acuity was 31.5 letters in the Avastin group and 32.7 letters in the Lucentis group. At one-year follow-up, meanvision was 43.6 letters in the Avastin group and 39.0 letters in the Lucentis group. Central subfield thickness (CST) improved in both groups. Subjects receiving Avastin had a baseline CST of 288.6 μm, which improved at one year to 235.8 μm. Subjects receiving Lucentis had a baseline CST of 340.8 μm, improving to 203.6 μm. Patients in the Avastin group underwent an average of 8.0 injections, while patients in the Lucentis group underwent a mean of 4.2 injections.

The researchers concluded that one-year outcomes of this head-to-head, randomized, prospective, doublemasked, controlled trial comparing Avastin and Lucentis failed to show a difference in visual outcomes for treatment of wet AMD. However, a significant difference in central foveal thickness was seen, and patients in the Avastin group required more injections over one year.

Some of the same researchers from the VA Boston Healthcare System also conducted a second study presented at ARVO. This study was a retrospective review of 34 wet AMD patients treated with Avastin or Lucentis in an OCT-guided regimen and evaluated over a one-year treatment period. Ten received Avastin while 24 were treated with Lucentis.

Pretreatment groups were matched in terms of visual acuity (logMAR 0.52 Avastin vs. logMAR 0.52 Lucentis), and central macular thickness (269 Avastin vs. 308 Lucentis). There was no statistically significant difference in the number of injections received at one year (5.3 Avastin vs. 5.6 Lucentis) and visual acuity outcomes were also similar (logMAR 0.38 Avastin vs. logMAR 0.40 Lucentis). No subjects in the Avastin group and one subject in the Lucentis group lost more than 15 letters on ETDRS chart.

Fourteen of the 34 patients required four or fewer injections, while 11 required seven or more. There was no statistical difference noted between the two groups when parametric values such as visual acuity, central macular thickness (CMT), lesion size and nonparametric values, such as presence of pigment epithelial detachment, hemorrhage and lesion locations were compared.

The researchers concluded that this case series of 34 patients yieldedsimilar injection numbers and similar visual acuity outcomes at one year. No pretreatment characteristics were identified that predict required injection number. Further studies with larger sample sizes are needed for confirmation of these findings.

Data on PDT/Lucentis Combinations

Fewer retreatments with combo therapies.

■ QLT, Inc. says data from two key studies show that PDT and ranibizumab used in combination can reduce the need for retreatment in wet AMD patients. However, the best vision gains were achieved from ranibizumab monotherapy.

Recently-released 12-month data from QLT's 321-person phase 3b DENALI study show that a combination of PDT and as-needed ranibizu - mab injections can reduce the number of injections needed to maintain vision gains. But at 12 months, average vision gains from monthly ranibizumab injections were superior (8.1 letters) to the combination regimen (5.3 letters with standard-fluence PDT and 4.4 letters for reduced-fluence PDT).

QLT said that most patients in the combination groups had a ranibizumabfree interval of at least three months during the study. The need for retreatment was based on a number of generally accepted retreatment criteria, including changes in central retinal thickness, presence of subretinal fluid, OCT assessment and decrease in visual acuity.

"This study adds support that Visudyne combination therapy can improve visual outcomes and may provide a treatment alternative that has the potential to reduce the treatment burden for patients with wet AMD," said Bob Butchofsky, president and CEO of QLT.

QLT has also released final results from the 24-month phase 2 phase RADICAL study, which compared ranibizumab monotherapy against several PDT/ranibizumab combinations. Though ranibizumab monotherapy produced the best mean vision gains, a "triple-therapy" regimen of half-fluence PDT, ranibizumab and dexamethasone required fewer retreatments (mean of 4.2 vs 8.9 monotherapy retreatments).

"The Visudyne/Lucentis combination therapy significantly decreased the number of retreatment visits required over two years, while patients' vision outcome was maintained within one line with an acceptable safety profile, compared with Lucentis alone," said Henry Hudson, MD, of Tucson, one of the two lead investigators for the study.

"The two-year results from the RADICAL study are consistent with the primary one-year results and demonstrate that combination therapy is a potential treatment option for patients with wet AMD," said Allen C. Ho, MD, a professor of ophthalmology at Philadelphia's Wills Eye Institute, the other lead investigator for the study.

Radiation as a Supplement to Anti-VEGF

Study: potential for fewer injections

■ One of the primary current aims in the treatment of wet AMD is finding ways to reduce the number of intravitreal injections that a patient must undergo. To this end, researchers from King's College Hospital in London and Retinal Consultants of Arizona are conducting a study using macular epiretinal brachytherapy as a safe and effective supplement to anti-VEGF therapy. Their interim findings were reported at the recent ARVO meeting.

Fifty subjects with classic, minimally classic and occult lesions were enrolled. Patients must have had a minimum of three intravitreal anti-VEGF retreatment injections in the six months prior to enrollment, or five injections in 12 months before enrollment. Patients had received a mean of 12 total injections prior to enrollment.

All subjects in the study underwent pars plana vitrectomy and 24 Gy beta irradiation for four to five minutes, using a retractable strontium-90 source in an endoscopic probe (NeoVista, Freemont, CA).

Following this treatment, anti-VEGF injections were resumed if there was a five ETDRS letter loss, >50 μm central retinal thickness increase on OCT, new macular hemorrhage or new activity visible with fundus fluorescein angiography (FFA). Patients were retreated with the same anti-VEGF agent they were receiving prior to enrollment (bevacizumab 1.25 mg or ranibizumab 0.5 mg). Co-primary outcome measures were mean ETDRS visual acuity and mean number of anti-VEGF retreatment injections.

The researchers reported that, to date, 16 patients have reached the six-month milestone. Patients received a mean of two retreatment injections in that period, with 88% maintaining vision and 63% gaining vision. Mean visual gain was 1.2 letters (+3.0 in pseudophakes). There was an encouraging safety profile, with no retinal breaks, detachments or radiation retinopathy.

The researchers say these interim results suggest that epimacular brachytherapy may reduce the number of anti-VEGF retreatments required, while maintaining vision. However, further follow-up is needed. A large multicenter clinical trial is now underway.

The Future of Eye Examinations

■ It is always interesting to look at the capabilities of current technology and project its potential into the future. Alexander C. Walsh, MD, of the Doheny Eye Institute in Los Angeles, caught the attention of many attendees at the recent ARVO meeting with his vision of a single, patientoperated, OCT-based instrument that could screen from home for a broad range of eye diseases and deliver the results directly to an ophthalmologist's office.

"We believe that diagnostic technologies exist today that can decrease the cost, increase the efficiency and improve the quality of ophthalmic care and eye disease screening around the world. A simple, inexpensive, automated, patient-operated binocular device containing bilateral optical coherence tomography imaging systems has the potential to make the ophthalmic examination more objective, consistent, quantitative, documented and efficient," wrote Dr. Walsh in his presentation. "Furthermore, it has the potential to screen for diseases in all eye tissues, not just retinal diseases such as diabetic retinopathy."

Dr. Walsh wrote that Fourier domain OCT images of the entire central axis of the eye, so-called OCT biomicroscopy, may be able to replace many of the functions of a slit-lamp biomicroscope with permanently recorded, quantifiable, high-resolution OCT imaging.

He further contends that a selfadministered OCT-based binocular instrument with internal display screens and buttons for input may be able to perform such quantitative analyses as pupillometry, extraocular motility, measurements of strabismus and many or all of the functions of the following diagnostic tests: visual acuity testing, autorefraction, static perimetry, kinetic perimetry, confrontation visual fields, ocular alignment and motility testing, corneal topography, corneal pachymetry, gonioscopy, color vision assessments, Amsler grid testing, reading speed assessments, contrast sensitivity testing, stereoacuity testing, suppression testing, exophthalmometry, and optical coherence tomography.

Dr. Walsh posits that, given the feasibility of patient-administered testing, "this single OCT-based, binocular instrument may be capable of collecting enough data outside of a clinical setting to support remote, comprehensive, electronic ophthalmic evaluations."

Looking out even further with a global view, Dr. Walsh writes that "an automated version of this device capable of making point-of-care risk assessments and providing immediate results and direction to the patient may also be one method of enabling accessible, affordable eye disease screening even in the world's poorest countries where blindness is more common."

For these reasons, Dr. Walsh believes that self-administered testing using advanced OCT technology has the potential to reduce the cost, increase the efficiency, and improve the quality of ophthalmic care around the world.

He concludes by writing that his somewhat futuristic ideas are primarily intended to stimulate discussion and encourage the development of alternatives to current eye examination technologies.

Anti-VEGF and Reading Speed

■ Hundreds of patients who participated in Genentech's phase 3 trials for macular edema associated with branch and central retinal vein occlusion (BRVO and CRUISE) were also tested to determine if treatment with ranibizumab could have an effect an reading speed.

Using a specially designed reading test, BRAVO patients who received 0.3 mg of ranibizumab monthly for six months showed a mean improvement of 21.9 words per minute from baseline at six months, while patients receiving the 0.5 mg dose of ranibizumab showed a mean improvement of 31.3 words. BRVO patients who had sham injections showed a mean improvement of 15.0 words at six months.

CRUISE patients who received the 0.3 mg dose showed a mean improvement of 23.7 words per minute after six months, which was better than the 0.5 mg cohort, which demonstrated mean improvement of 20.6 words. The sham group improved by 8.1 words per minute.

Researchers, who presented this data at the recent ARVO meeting, concluded that improved reading speed following ranibizumab therapy indicated a direct patient performance metric of reading ability and visual function. RP

IN BRIEF

"Treat and extend" study. Researchers from Wills Eye Hospital and Temple University used a "treat and extend" (TER) regimen with 74 wet AMD patients to reduce the number of intravitreal injections needed to maintain vision gains. They presented their findings at ARVO.

The patients were treated every four weeks with bevacizumab until no intraretinal or subretinal fluid was observed on OCT. The follow-up interval was then extended continuously by two weeks until signs of exudation recurred. Exclusion criteria included history of photodynamic therapy. Main outcomes measured included initial and final visual acuities, number of injections, and maximum treatment interval.

The mean Snellen visual acuity was 20/230 at baseline, improving significantly to 20/118 at six months, 20/109 at 12 months and 20/106 at 24 months follow-up. The mean number of injections over the first year was 7.27. The OCT central retinal thickness de creased from 316 microns to 239 microns. Using a TER regimen as outlined in this study, the annual direct medical cost per patient is $6,160.13. The annual direct medical cost per patient treated with ranibizumab utilizing MARINA and PrONTO trial protocols is $28,314.16 and $15,880.07, respectively.

The visual outcomes were similar to the these pivotal trials, but with fewer patient visits and injections.

Vitrectomy for retained lens fragments. Retained lens fragments resulting from a cataract surgery complication are best removed sooner rather than later, according to a study presented by researchers from the Duke University Eye Center at the recent ARVO meeting.

In a retrospective review of 73 patients referred to the Duke Eye Center for posterior capsule rupture and retained lens fragments, patients who underwent a pars plana vitrectomy within seven days after cataract surgery typically had better final visual acuity than those patients who had PPV at eight to 30 days.

The researchers found no other significant differences between these interval groups in outcomes or complications. They also cautioned that patients referred to a retina specialist with retained lens fragments may present with significant morbidity, including endophthalmitis, retinal detachment, corneal edema and elevated IOP.

Iridex MicroPulse protocol for DME. Iridex Corporation said new clinical data show that results obtained in the treatment of DME using an Iridex laser and MicroPulse treatment protocol were superior to those obtained using the recognized standard of care Early Treatment of Diabetic Retinopathy Study (ETDRS) laser protocol.

At one year, the prospective, randomized study demonstrated that a MicroPulse protocol was as effective as the ETDRS protocol in the treatment of DME. Moreover, Iridex said retinal sensitivity improved in eyes in the MicroPulse-treated group and decreased in the ETDRS treated group, with no detectable signs of laser damage to retinal tissues in eyes in the MicroPulse group while all eyes in the ETDRS group developed localized laser scars.

Lucentis approved for BRVO and CRVO. Following a six-month priority review, the FDA has approved ranibizumab for treatment of macular edema due to retinal vein occlusion, The approval includes both branch and central retinal vein occlusion.

"In the Lucentis RVO clinical trials, significantly more people treated with monthly Lucentis showed sustained vision improvement during the six-month study, with an effect seen as early as seven days," said Hal Barron, MD, Genentech's executive vice president of global development and chief medical officer.

Please see a more extensive discussion of the treatments for RVO.

Refillable pump for sustainedrelease drug delivery. A group of California researchers led by retina specialist Robert Avery, MD, has successfully tested a miniature, implantable, refillable, remotely operated pump designed to precisely deliver very small quantities of medicine to the aqueous or vitreous cavity. They presented results at the recent ARVO meeting.

Researchers described a minidrug pump consisting of a drug reservoir, electrolysis chamber, battery, and electronics for controlling drug delivery via a cannula. Delivery is accomplished through microcurrents that hydrolyze water in the electrolysis chamber and force fluid out the drug reservoir. The device can be remotely programmed and activated. The battery can be inductively charged, and the drug reservoir can be refilled by an in-office procedure.

Prototypes of the pump were implanted in two dogs under the temporal conjunctivae with the cannula inserted into the anterior chamber. Glaucoma medications were used in this test. The pump was remotely activated on different days. Control eyes received the same medications topically. IOP was measured hourly for eight hours after administration. No complications were noted in the dogs after three months of observation. The reduction of IOP was comparable in both groups (pump vs. control).

The researchers concluded that it is possible to deliver drugs in a very controlled manner with this device. Potential applications include many retinal diseases currently treated with intravitreal injections. This platform will require further testing.

FDA approves Implantable Miniature Telescope for end-stage AMD. An intraocular prosthesis to improve vision in advanced AMD gained FDA approval, says manufacturer VisionCare Ophthalmic Technologies of Saratoga, CA. The implant is the basis of a new pa tient care program for end-stage patients called CentraSight, which includes a patient management process and access to reimbursement for patients and their physicians. The device is implanted in one eye as an outpatient procedure.

"This is truly a breakthrough technology for AMD patients as their treatment options have been limited until now," said Kathryn A. Colby, MD, PhD, ophthalmic surgeon at Massachusetts Eye and Ear Infirmary. "The clinical results from the pivotal FDA trial have proven we can place this tiny telescope prosthesis inside the eye to help patients see better and, for some, even to levels at which they can recognize people and facial expressions that they could not before."

VisionCare said that IMT patients achieved clinically meaningful gains in both visual acuity and quality of life. The magnification provided by the implant reduces the impact of the blind spot caused by end-stage AMD.

"The telescope implant represents a new category of treatment for this severely visually impaired population," said Allen W. Hill, CEO of VisionCare. "We are excited to now provide this new technology and related CentraSight treatment program to the ophthalmic community to help their patients with this devastating disease."

Treating severe floaters. Researchers from Retina Consultants of Alabama and the University of Alabama at Birmingham School of Medicine reported at the recent ARVO meeting that vitrectomy can significantly improve the quality of life and quality of vision for patients with vitreous debris (floaters).

The researchers reported that 16 consecutive patients had sutureless vitrectomy for vitreous debris. Each patient completed a 25-item visual function questionnaire (NEI VFQ-25), as well as having both preoperative and postoperative best-corrected logMAR visual acuity measurements.

Sutureless vitrectomy for vitreous debris improved the NEI VFQ-25 composite score as well as scores on 10 out of 12 subscales (p=0.001). The postoperative NEI VFQ-25 composite score significantly correlated with logMAR BCVA (p=0.001). The mean preoperative logMAR BCVA was 0.40 (range 0.00 to 1.30), which improved to a mean postoperative BCVA of 0.25 (range 0.00 to 1.30). All patients noted a subjective improvement in visual acuity postoperatively.

The researchers concluded that patients experienced improved quality of life and visual acuity after undergoing 25-gauge sutureless vitrectomy for removal of vitreous debris. They suggest that vitrectomy surgery should be considered as a viable treatment option for patients with symptomatic vitreous floaters.

Iluvien insert shows 30-month benefit. Alimera files NDA. Alimera Sciences, Inc. said a new analysis of data from its phase 3 (FAME) clinical trials for Iluvien, the company's investigational intravitreal insert being studied for DME, indicates that patient vision continues to improve significantly over 30 months.

Alimera has now filed an NDA for Iluvien as a treatment for DME and has requested priority review.

At month 24, 31% of the low-dose patients had improved vision of 15 letters or more, while at month 30, with a sample size of 123 patients, an improvement in visual acuity of 15 letters or more was seen in 40% of the patients. Statistical significance versus control was seen by three weeks among the observed cases, and this significance was maintained through month 30. The complete 36- month dataset will be presented after the trial concludes in October.

Retisert well tolerated in patients. In a presentation given at ARVO, researchers at Massachusetts Eye Research and Surgery Institution found the Retisert implant to be a well-tolerated device, enabling longterm corticosteroid treatment of noninfectious inflammation. A review evaluated 64 patients with a history of uveitis who received Retisert implants from 2005 to 2009 at the hospital.

The reviewers state "the device dem onstrates a role in the decreased dependence on, and even potential dis continuation of, systemic immunotherapy for the treatment of uveitis." They add that although Retisert was found to be generally well-tolerated, potential complications including elevated IOP were found to be common.

RP patients read words with device. Of 32 retinitis pigmentosa patients with bare light perception who have thus far been fitted with the Argus II Retinal Prothesis, many can now distinguish single letters and others can read three- and four-letter words. The letters and words are displayed in white in 350 point Century Gothic font against a black background. As reported at the recent ARVO meeting, an open set of words was used and displayed in random order at a distance of 12 inches.



Retinal Physician, Issue: July 2010