Article Date: 6/1/2011

Allergan Licenses Wet AMD Drug
SUBSPECIALTY NEWS

Allergan Licenses Wet AMD Drug

DARPin protein in phase 2 trial.

■ Allergan and Molecular Partners AG have entered into a license agreement for MP0112, a phase 2 proprietary therapeutic DARPin protein targeting VEGF, under investigation for the treatment of retinal diseases.

Under the agreement, Allergan obtains exclusive global rights for MP0112 for ophthalmic indications. The parties will work together during phase 2b development, while Allergan will be responsible for phase 3 development and commercialization activities. Molecular Partners will receive an upfront payment of $45 million and is further entitled to receive additional payments of up to an aggregate of $375 million upon meeting certain development, regulatory and sales milestones.

Data on MP0112 from two separate phase 1/2a trials in wet AMD and DME, presented at ARVO, showed that MP0112 is well tolerated and has a potentially long-lasting effect on vision gain after a single injection. In the studies, for most patients in the cohorts treated with the higher dose of the investigational compound, the potential beneficial effect on visual acuity lasted for approximately 16 weeks.

In the DME trial, initial results from an interim analysis conducted for the first 15 patients completing the 16-week study time point have shown promising efficacy in spite of the majority of patients having longstanding, refractive DME. Six of 15 patients showed an improvement of 10 or more letters in BCVA at week four, week 12 and week 16. In addition, eight of 15 patients showed an improvement in OCT of greater than 50 µm at week four, and four of 15 patients at week 12 and 16.

In the wet AMD trial, initial results from an interim analysis conducted for the first 32 patients completing the 16-week study time point have shown clear OCT responses (mean decreases in central retinal thickness were −95 µm and −111 µm at week 4 in the highest two dose groups, 1 mg and 2 mg, respectively) and that the OCT decrease was maintained in seven of eight patients in the highest two dose groups for 12 to 16 weeks.

Fibrin Glue in Vitreoretinal Surgery

A replacement for sutures?

■ Two researchers from the retina service, Asociacion Para Evitar La Ceguera in Mexico City set out to determine if fibrin glue could serve as a satisfactory—and possibly improved—substitute for sutures in a range of vitreoretinal surgeries.

Their data included 178 eyes of 162 patients who underwent vitreoretinal surgery during a six-month period in 2010. Preoperative diagnoses encompassed the following: proliferative diabetic retinopathy (104 eyes), rhegmatogenous retinal detachment (18 eyes), macular hole (12 patients), epiretinal membrane (8), luxation of cataractous nucleus and cortex (8), IOL luxation (6), penetrating trauma (4), silicone extraction (4), phaco+ IOL+vitrectomy+Ahmed valve implant (2), and vitreous biopsy (2). Fifty-two eyes required silicone oil and two heavy silicone. Sixty-four eyes had a gas tamponade and 62 saline solution.

One hundred and seventy-two patients underwent 23-gauge vitrectomy, four patients 29-gauge, and two 25-gauge, with all of the procedures performed using Alcon's Accurus surgical system.

Fibrin glue was used in all of the wounds: sclerotomies, scleral wound for IOL extraction, conjunctiva peritomy for buckle, and conjunctiva in Ahmed valve implant.

“We did not used any suture in all 178 eyes in the different procedures,” wrote the researchers in their ARVO presentation. “There was no leakage in sclerotomies in [the] immediate postoperative [phase] or after. We found no inflammatory reaction or infection. One patient presented a small dehiscence of the wound that was corrected with a small amount of fibrin glue.”

The researchers concluded that fibrin glue reduces surgical time, is a good sealant and is safe, with minimal allergic or toxic reactions and inflammation. They found that fibrin glue minimizes bleeding, is easy to undo and eventually disappears.

“This small series shows us that fibrin glue is a viable alternative for tissue co-optation in vitreoretinal surgery. However, further studies are required before fibrin glue takes the place of sutures,” they wrote.

Double-dose Lucentis has Limited Benefits

Improvement in CFT but not BCVA.

■ Jeffrey Chang, MD, and Jeffrey Heier, MD, conducted a retrospective, non-randomized study of 29 eyes of 29 patients with wet AMD who had not responded well to multiple treatments of the normal 0.5-mg dose of Lucentis and/or Avastin and were then treated with multiple 1-mg doses.

The need for retreatment was physician-dependent and determined after clinical assessment, based upon best-corrected visual acuity (BCVA) and central foveal thickness (CFT) as determined by optical coherence tomography. The 29 treated eyes received an average of 2.7 injections of high-dose intravitreal Lucentis. The average initial CFT and BCVA were 387 microns and 20/74, respectively. Post-treatment mean CFT and BCVA were 344 microns and 20/75, respectively, with a minimum one month follow-up. No adverse events were noted.

The researchers, presenting at ARVO, found that patients recalcitrant to multiple prior Lucentis and/or Avastin treatments experienced an average improvement in CFT after an average of 2.7 injections of high-dose Lucentis at monthly intervals. The average BCVA remained stable.

“These findings suggest that there may be a subset of patients minimally responsive to prior treatment that may benefit from high-dose [Lucentis]. Greater numbers of patients and longer follow-up are required to confirm these results,” Drs. Chang and Heier concluded.

Genentech is currently conducting the HARBOR trial, a study to determine the benefits of increasing the Lucentis dose to 2 mg.

Wet AMD: Asymptomatic Fellow Eyes

Occult fluid indicates need for treatment.

■ Building on previous studies showing that patients with unilateral wet AMD were at risk for the disease in the fellow eye, Del Priore et al. sought to determine if early treatment of the asymptomatic fellow eye could provide visual benefits.

The researchers conducted a retrospective chart review of patients who had subretinal or intraretinal fluid as indicated by SD-OCT testing.

“We identified 28 eyes of 28 patients with known neovascular AMD in one eye, in whom SD-OCT of the fellow eye detected asymptomatic subretinal or intraretinal fluid during one of their periodic follow-up visits,” the researchers reported in their ARVO presentation.

Initial BCVA of these asymptomatic eyes ranged from 20/20 to 20/40. Occult neovascularization was present in all 12 eyes that underwent fluorescein angiography prior to treatment. All patients were treated with intravitreal Avastin and/or Lucentis using a variety of treatment regimens (monthly, three monthly injections followed by quarterly, “treat and extend” or SD-OCT-guided as needed). The average number of intravitreal injections in the second eye was 4.0 per eye over a mean follow-up of 43 months. There was a wide range in the number of injections received by individual patients (ranging from one to 24 injections) due to the different treatment protocols. Final BCVA ranged from 20/20 to 20/70.

The researchers concluded that “routine SD-OCT imaging of the fellow eye of high-risk patients who have already exhibited neovascularization in their first eye allows for early detection of subretinal or intraretinal fluid in some patients prior to the onset of symptoms. Visual acuity results are excellent if treatment of asymptomatic fluid is initiated prior to the onset of significant visual loss.”

The researchers cautioned that larger clinical trials are necessary to determine the natural history of asymptomatic fluid, and to delineate the benefits and costs of SD-OCT based screening and subsequent early treatment.

Endophthalmitis After Intravitreal Injection

Large-scale study at Bascom Palmer.

■ A review of more than 58,000 intravitreal injections of Lucentis and Avastin at Bascom Palmer facilities over an almost six-year period found that only 12 endophthalmitis-suspect cases were reported.

The study, a retrospective consecutive case series from the university-based referral center and three university-owned satellite clinics, recorded rates of endophthalmitis, clinical outcomes and microbiological features.

Twelve cases of clinically suspected endophthalmitis were identified out of a total of 58,453 injections. Eleven of the 12 cases presented within three days of the injection. Of the seven culture-positive cases, five were due to Streptococcus species, one was due to Staphylococcus epidermidis, and one was due to Bacillus non-anthracis.

Of the culture-positive cases, three achieved visual acuity of 20/100 or better, but four had hand motions or worse vision at last follow-up. In four of the five Streptococcus cases, final visual acuity was hand motions or worse. Four of the five culture-negative cases, by contrast, achieved visual acuity better than 20/100. The rate of clinically suspected endophthalmitis was 0.023% after Avastin and 0.036% after Lucentis.

The researchers concluded that there was a very low rate of endophthalmitis after intravitreal injection of anti-VEGF agents. Patients typically presented within three days of injection. Streptococcus species was the most common bacteria isolated and it was generally associated with poor visual outcomes.

The findings were presented at the recent ARVO meeting.

Eating Fish Cuts Women's AMD Risk

Large, long-term study shows benefits.

■ A major study encompassing more than 38,000 women who were followed for an average of 10 years indicates that those women who ate more fish had a significantly lower risk of developing macular degeneration.

The research effort was led by William Christen, ScD, as part of the Harvard School of Medicine's Women's Health Study. The stated rationale for the study was that “cardiovascular disease and AMD have been hypothesized to share similar mechanisms and risk factors. The dietary intake of fish, and specifically the omega-3 fatty acids concentrated in fish (DHA and EPA), has been linked with reduced rates of cardiovascular events in epidemiologic studies and could also have a similar beneficial effect in AMD. These fatty acids are known to exert anti-inflammatory, anti-atherosclerotic and antithrombotic effects on the vasculature and may help to maintain or improve choroidal blood flow in the eye.”

The study began in 1993 with 38,022 apparently healthy female US health professionals who were than 45 years of age or older completing a detailed, 131-item “food-frequency” questionnaire that included questions on the respondents' consumption of various foods. Respondents were asked to report average consumption of each food along with typical portion size. The women in the study, none of whom had AMD at baseline, were followed-up annually and asked to report on any new medical diagnoses.

The researchers reported recently in the online edition of Archives of Ophthalmology “a total of 235 cases of AMD, most of which were characterized by some combination of drusen and retinal pigment epithelial changes, were confirmed during an average of 10 years of follow-up.”

Women who reported eating one or more servings of fish each week were 42% less likely to develop AMD than women who ate fish less than once a month. In terms of types of fish eaten, canned tuna, sardines, salmon and dark-meat fish appeared to offer the most benefit.

The researchers concluded that regular consumption of the fatty acids DHA and EPA was associated “with a significantly decreased risk of incident AMD and may be of benefit in primary prevention of AMD.”

IN BRIEF
Can patients recognize a sham injection? Adam R. Glassman of the Diabetic Retinopathy Clinical Research Network set out to determine if patients in a clinical trial can tell whether they are receiving a real or sham injection.
He describes a sham injection as the hub of a syringe (no needle) pressed against the conjunctiva to simulate the force of a real injection.
Of the patients with one study eye who received a sham injection, only 10% were correct in recognizing the injection as sham. However, in patients with two study eyes, 24% were able to correctly recognize that they had received one sham injection.
Mr. Glassman, presenting at ARVO, concluded that successful masking is dependent on “following a detailed injection procedure that care fully mimics a true injection procedure.” He found that masking is less successful when one eye is receiving a real injection and the other a sham, or when the patient has had both real and sham injections.
Anti-VEGF in end-stage wet AMD. Researchers from Retina Vitreous Associates of Los Angeles and New England Retina Associates of Old Greenwich, CT, sought to determine the value of anti-VEGF in patients with BCVA of 20/400 or worse.
Twenty-two eyes of 22 patients with previously untreated wet AMD were studied, with seven patients initially presenting with BCVA of 20/400 and 15 presenting with BCVA worse than 20/400. Exclusion criteria included subretinal fibrosis involving central fovea, subfoveal hemorrhage greater than one disc area, and presence of other ocular pathology reducing vision.
Mean follow-up was 16.1 months and mean number of injections per patient was 7.3. At last follow-up, five eyes had increased BCVA vision of 20/40 or better, three were between 20/50 and 20/100, four were 20/200, six were 20/400 and four were worse than 20/400.
Presenting at ARVO, the researchers concluded that, in the absence of subfoveal fibrosis or extensive hemorrhage, anti-VEGF “is beneficial to previously untreated [wet AMD] and severe vision loss. Treatment decisions should not be based on visual acuity but on the characteristics of the lesion.”
Biweekly anti-VEGF injections. In an interesting small study, retina specialists from Wills Eye Institute gave biweekly anti-VEGF injections to wet AMD patients who had not responded well to monthly injections of Lucentis or Avastin.
Thirteen eyes of 13 patients who had previously received a mean of 18.8 injections were dosed on a biweekly basis, receiving four injections in two months. Mean baseline visual acuity was 20/93 and mean baseline central foveal thickness was 168 microns.
After eight weeks and four injections, mean visual acuity improved to 20/57 and mean central foveal thickness decreased to 162 microns. There were no adverse events during the study period.
The researchers, presenting at ARVO, concluded that biweekly injections can be visually beneficial and may be an option for anti-VEGF non-responders with wet AMD.
VEGF Trap CRVO efficacy confirmed in second trial. Regeneron Pharmaceuticals and Bayer Health-Care announced positive top-line results for VEGF Trap-Eye in the phase 3 GALILEO study in patients with macular edema due to CRVO.
In GALILEO, the primary endpoint at week 24 was achieved: 60.2% of patients receiving monthly VEGF Trap-Eye 2 mg gained at least 15 letters of vision from baseline, compared to 22.1% of patients receiving sham.
Aggressive anti-VEGF treatment for DME. A team of researchers led by Diana Do, MD, of the Wilmer Eye Institute, offered patients in the READ2 trial for DME an opportunity to extend the 24-month trial by another year with monthly monitoring rather than the every two months PRN monitoring called for in the READ2 trial.
A total of 74 patients completed the additional 12 months, with ranibizumab retreatment provided if foveal thickness was greater than 250 microns. Though the patients had initially been separated into three different treatment protocols, the researchers found that allowing monthly anti-VEGF treatment generally had a beneficial effect in improving BCVA and reducing foveal thickness. Presenting at ARVO, they concluded that “many patients with DME require frequent [anti-VEGF] injections to optimally control edema and maximize vision.”
Using bevacizumab for ROP. Researchers from the Asociacion Para Evitar la Ceguera in Mexico sought to describe the prevalence of blindness in retinopathy of prematurity (ROP) patients treated with off-label intravitreal bevacizumab.
At ARVO, they reported on 161 premature infants at the neonatal intensive care unit of two secondary hospitals who underwent eye examinations between four and six weeks of age. Twenty-nine eyes required treatment (stage III, threshold or prethreshold ROP), which consisted of 0.03 cc of intravitreal bevacizumab under topical anesthesia.
After one-year, none of the treated eyes developed blindness or any other serious ocular complication.
The researchers concluded that the low level of blindness prevalence in ROP patients treated with bevacizumab suggests that “intravitreal antiangiogenic therapy seems to be a promising treatment as monotherapy for ROP patients with no access to technological devices such as laser or cryo to provide conventional treatment for this devastating disease.”
Could the presence of drusen be a key to Alzheimer's diagnosis? Researchers from London, presenting at ARVO, reported a correlation between peripheral hard drusen and Alzheimer's disease (AD).
Using the Optos P200C for ultra-wide angle retinal imaging in 55 AD patients and 48 controls, the researchers found peripheral hard drusen in 14 of the AD patients but in only two of the control group.
The researchers wrote that, with further study, pathological changes in the periphery “might become a valuable tool in detecting and monitoring the progression of AD.”
NEI releases 72,000 AREDS images. The National Eye Institute, in collaboration with the National Center for Biotechnology Information (NCBI), has made available more than 72,000 lens photographs and fundus photographs of the back of the eye, collected from the participants of the Age-Related Eye Disease Study (AREDS).
These images are now accessible to scientists through NCBI's online database of Genotypes and Phenotypes, known as dbGaP, which archives data from studies that explore the relationship between genetic variations (genotype) and observable traits (phenotype). Though study descriptions and protocols are publicly accessible, researchers must apply for controlled access to deidentified information about study subjects, including the new images.
“The availability of AREDS images through dbGaP may transform the way we conduct vision research,” said NEI director Paul A. Sieving, MD, PhD. “Scientists can increase their understanding of the impact of genetics and gene/environment interactions on blinding eye disease progression.”
QLT drug shows promise in LCA. QLT announced positive preliminary results from its phase 1b proof-of-concept clinical trial of QLT091001 for the treatment of Leber's congenital amaurosis (LCA). Analysis of data from 12 subjects with LCA treated with QLT091001 for seven days was conducted to determine improvements in two measures of visual function: visual acuity and visual fields. The study demonstrated that treatment with QLT091001 resulted in clinically meaningful improvement in either or both visual acuity and visual fields in eight of the 12 subjects.
IMT wins innovation award. VisionCare Ophthalmic Technologies, a developer of advanced visual prosthetic devices, announced that the Implantable Miniature Telescope (IMT), designed to improve vision in patients with end-stage AMD, has been named “Best of What's New” by Popular Science magazine.
VisionCare's first-of-its-kind telescope implant is integral to a new patient care program, CentraSight, for treating patients with end-stage macular degeneration. The telescope implant is the first and only prosthetic treatment for AMD patients who progress to end-stage disease.
In its annual contest, Popular Science evaluated companies and products in 11 different categories to identify innovations with potential to positively impact the future and push the envelope of what was not thought to be possible in the previous 12 months. Annually, the magazine's “Best of What's New” honors the top 100 innovations. The IMT is a winner in the health category.
The telescope implant earned FDA approval in 2010.
Eyetech gets grant for sustained-release Macugen. Eyetech has been awarded a $245,000 grant under a federal program called the Qualifying Therapeutic Discovery Project. The company says that the grant will be used to support the development of an extended-release formulation of the FDA-approved wet AMD drug Macugen using microparticles technology.
Eyetech is already collaborating with SurModics Pharmaceuticals, a drug-delivery company, to develop the extended-release version of Macugen. The goal of the Macugen extended-release formulation is to decrease the frequency of dosing from every six weeks to every four to six months.


Retinal Physician, Issue: June 2011