Old Drug Could Be New DME Treatment
Oral minocyline proves effective.
By René Luthe, Senior Associate Editor
■ Minocycline, a broad-spectrum antibiotic and anti-inflammatory used primarily to treat acne, may be a safe and effective treatment for diabetic retinopathy, according to research presented at the 2012 ARVO meeting. Investigators led by Catherine Cukras, MD, of the NIH, note that while the pathogenesis of DR is still not understood, it has been prominently associated with processes of chronic inflammation.
Previous research, Dr. Cukras says, indicates that microglia is involved in inflammatory processes in the retina, including diabetic macular edema. Inflammation activates microglia, the resident immune cells of the retina, which are in close proximity to DR lesions (including DME). Studies of animal models of DR have shown that therapies that inhibit microglial activation can decrease retinal inflammation and neuronal death.
Because minocycline, a drug also used in the treatment of Lyme disease and rheumatoid arthritis, is already commonly used and FDA-approved, “it was feasible for us to design a study to investigate the role of inhibiting microglia in a human clinical trial,” Dr. Cukras explains.
Five subjects with DME involving the center of the fovea were included in the continuing prospective, openlabel, Phase1/2 pilot study, and dosed with 100 mg oral minocycline bid for at least six months (the study will treat the subjects for 24 months). The primary outcome measure was change in BCVA at six months from baseline. Additional measures were central macular thickness as measured by OCT and area of late leakage on fluorescein angiography, as well as safety outcomes.
At month six, five out of five study eyes and four out of five fellow eyes demonstrated increases in BCVA from baseline. The mean improvement in BCVA was +5.8±2.4 (mean + standard error) letters for study eyes and+5.1±1.4% for all eyes. One eye improved by > 15 letters.
Mean measures of vision and DME thickness also improved. Mean OCT central macular thickness decreased by -8.1±6.5% for study eyes and -7.3±5.2% for all eyes. Late leakage on FA decreased in 5/5 of study eyes and in 9/10 of all eyes. The drug was well tolerated, with few adverse events reported. Thus, minocycline “as a primary treatment was associated with improved visual function, central macular edema and vascular leakage,” the investigators conclude. And its oral delivery would make it a much more patient-friendly therapy for DME than currently available options.
After the six-month point, Dr. Cukras reports, ancillary treatment of laser and/or anti-VEGF therapy will be added to the minocyline treatment, making its role more complicated to interpret. “For the future, we would like to study minocycline treatment in a larger, random, placebo-controlled study, and hopefully we will have an avenue to do this.”
|■ Intraocular foreign bodies and endophthalmitis. In an effort to determine the incidence of endophthalmitis in patients who were treated for a traumatic retained intraocular foreign body (IOFB), researchers at Bascom Palmer Eye Institute analyzed all such cases over a 10-year period.|
A total of 108 eyes with IOFBs were identified. Mean initial BCVA was 20/600 (range 20/20 to NLP), and final mean BCVA was 20/210 (range 20/20 to NLP). Endophthalmitis occurred in seven of 108 eyes (6.4%) at presentation, and risk was higher with an injury during yard work with vegetable matter exposure. All eyes with IOFBs involving the posterior segment received intravitreal antibiotics at time of initial management, and there were no cases of endophthalmitis after initial management.
The researchers, who presented their findings at the recent ARVO meeting, concluded that risk factors for endophthalmitis included vegetable matter-related injury and delayed time interval from injury to initial management. In the current study, intravitreal antibiotic administration at the time of initial management was associated with the absence of postoperative endophthalmitis.
■ Iluvien approved in Portugal. Alimera Sciences' Iluvien implant for the treatment of DME has now been approved in Portugal. This follows recent approvals by regulatory authorities in the UK and Austria.
Anti-PDGF Effective in Combo Therapy
Superior data to Lucentis alone.
■ Ophthotech Corp. said results from a large phase 2b clinical trial of its anti-platelet derived growth factor (anti-PDGF) drug in combination with Lucentis show statistically significant superior efficacy over Lucentis monotherapy for the treatment of wet AMD.
In a prospective, randomized, controlled trial of 449 patients with wet AMD, Ophthotech's Fovista anti-PDGF therapy (1.5 mg), administered in combination with Lucentis anti-VEGF therapy, met the pre-specified primary efficacy endpoint of mean vision gain. Patients receiving the combination of Fovista (1.5 mg) and Lucentis gained a mean of 10.6 letters of vision on the ETDRS standardized chart at 24 weeks, compared to 6.5 letters for patients receiving Lucentis monotherapy, representing a 62% additional benefit. No significant safety issues were observed for either treatment group in the trial.
Enhanced visual outcomes of Fovista (1.5) anti-PDGF combination therapy as compared to Lucentis monotherapy were demonstrated at every monthly timepoint. In addition, the relative magnitude of visual benefit continued to increase over time. The visual benefit of anti-PDGF (1.5) combination therapy compared to Lucentis monotherapy was greater at the six-month timepoint than at the three-month timepoint. The increasing divergence of the efficacy curves suggests the benefit of repeated anti-PDGF combination therapy. A classic dose-response curve was observed.
“This is a truly remarkable finding for patients with wet AMD. To achieve a 62% relative visual benefit over anti-VEGF monotherapy is extraordinary,” commented retina specialist Carmen A. Puliafito, MD, Dean of the Keck School of Medicine at the University of Southern California. “The very compelling and robust results of this well-executed study validate PDGF as an important target for wet AMD and set the stage for a new era of combination therapy via co-formulation or fixed-combination delivery.”
The robust benefit of Fovista (1.5 mg) combination therapy over Lucentis monotherapy was consistent across all subgroups including those analyzing baseline vision, lesion size and the proportion of patients gaining 1, 2, 3, 4 and 5 lines of vision (ETDRS standardized chart). An average absolute benefit of 7.4% over Lucentis monotherapy was present across all ETDRS lines of vision gain. In addition, a relative benefit of 25% over Lucentis monotherapy was attained in patients who gained 3 or more lines of vision, with 69% and 178% relative benefit in patients gaining 4 or more and 5 or more lines of vision, respectively.
Though this trial was specific to combination therapy with Lucentis, Ophthotech is said to believe that Fovista could also be effective in combination with the other widely used drugs for wet AMD, Avastin and Eylea.
|■ Multiple Ozurdex effective for two diseases. Ophthalmologists at Weill Cornell Medical College studied a total of 13 patients who had received two or more Ozurdex (Allergan) implants for either posterior non-infectious uveitis or RVOrelated macular edema.|
The researchers, presenting at ARVO, found the median time to retreatment for the uveitis patients was 16.4 weeks, while the median time to retreatment for the macular edema patients was 20.3 weeks. All of the RVO patients showed improvement in VA and decrease in macular edema. The uveitis patients demonstrated reduction in inflammation and improved VA. One patient with macular edema received five Ozurdex implants. None of the uveitis patients received more than three.
■ Tissue-sparing laser procedure. Iridex Corp. said MicroPulse Laser Therapy, using the IQ 577 laser coupled with EndoProbe instrumentation, was successfully performed by Sam Mansour, MD, medical director of the Virginia Retina Center. Iridex says this is the first time tissue-sparing laser therapy has been delivered through an intraocular fiber-optic probe in a surgical setting.
Dr. Mansour said “Endo-MicroPulse laser surgery is a more direct and controlled method than slit lamp delivery. It gives me the flexibility to treat my most difficult cases without compromising the retinal tissue. It is effective in cases of very thin retinas due to its ability to preserve tissue rather than destroy it.”
Outcomes of Unoperated VMT
Most eyes do not require surgery.
■ Researchers at Bascom Palmer Eye Institute followed 38 eyes of 26 patients to determine the visual and anatomic outcomes of vitreomacular traction (VMT) that was not treated surgically.
The study, which was presented at the recent ARVO meeting, involved 13 male and 13 female patients with a mean age of 75 years. Mean follow-up was 589 days.
At the initial visit, patients had a mean BCVA of 20/50, and 13 eyes [34%] had Grade 1 VMT [no cysts], 20 eyes [53%] had Grade 2 VMT with cysts, and five eyes [13%] presented with Grade 3 VMT with subretinal fluid. During the time of follow-up, only one eye underwent surgery due to worsening vision. At final visit, mean BCVA was 20/40, with 24 eyes [64%] remaining stable by OCT. Only five eyes [13%] worsened in their anatomic VMT grading by OCT.
The researchers concluded that the unoperated clinical course of VMT is relatively stable over the course of the 16-month mean follow up in this study. “Mean initial and last follow-up visual acuity were similar,” they concluded. “There was a low rate of progression from mild to severe grades of VMT that may need vitreoretinal surgery.”
The researchers believe that “many, if not most, VMT patients can be followed nonsurgically.” Surgical indications are not clearly defined but surgery might be considered for eyes with progressive visual or anatomic worsening. In addition, nonsurgical injection therapies are now becoming available, but indications for their use have not been well established.
Endogenous Endophthalmitis From Yeast
A review of 20+ years of cases.
■ Though endogenous endophthamitis accounts for only a relatively small percentage (5% to 15%) of all endophthalmitis infections, it is a very serious disease that usually results in poor visual outcomes. In a study presented at the recent ARVO meeting, Bascom Palmer researchers led by Jayanth Srihar, MD, reviewed more than 20 years of their culture-proven unilateral or bilateral endogenous endophthalmitis cases caused by yeast.
Study criteria were met in 51 eyes of 39 patients. Patients had a mean follow-up of 16.7 months from presentation to last follow-up visit.
The researchers reported that decreased vision was the most common presenting symptom (74.3%) followed by redness (46.1%) and pain (38.5%). More than two-thirds of these patients had a current or recent hospitalization at the time of diagnosis. Recent surgery was the most common identified risk factor (31.6%) followed by cancer (23.7%). None of the patients were diagnosed on routine screening for fungemia. Diffuse anterior and posterior inflammation was the most common finding on examination of affected eyes (64.7%) followed by focal posterior inflammation (23.5%). Hypopyon was noted in only 5.8% of affected eyes.
Initial treatment consisted of a combination of medical and surgical treatment in 33.3% of eyes. About 37% of eyes received medical treatment consisting of systemic antifungal therapy, intravitreal injection of antifungals, or both, while 43.1% of eyes underwent vitrectomy with or without lensectomy, with or without intravitreal injection.
The most common organism cultured was Candida albicans (87.2%) followed by Candida tropicalis (7.7%) and Cryptococcus neoformans (5.1%). Blood cultures were positive in 17.9% of patients.
Visual acuity on presentation was 20/200 or better in 41.3% of eyes. Visual acuity of 20/200 or better was present in 61.3% of eyes at last follow-up. Retinal detachment occurred in 29.4% of eyes.
The researchers noted that in this study of endogenous endophthalmitis caused by yeast, Candida albicans was the predominant etiology. Decreased vision was the most common presenting symptom. Endogenous endophthalmitis is associated with poor visual acuity outcomes despite early and appropriate management. Retinal detachment is a frequent event in the clinical course.
Sleep Apnea and Anti-VEGF
This disorder affects efficacy.
■ Untreated sleep apnea is known to be responsible for a number of concerning anatomic and functional changes. Researchers at the University of Louisville set out to determine whether sleep apnea could have any effect on anti-VEGF treatments used to treat wet AMD. Their study involved analyzing the functional and anatomical response to anti-VEGF therapy with bevacizumab before and after treatment of obstructive sleep apnea (OSA).
Twelve wet AMD patients with untreated OSA were treated with intravitreal bevacizumab every six weeks. Clinical examinations and OCT at six-week intervals were used to assess the anatomical and functional outcome for up to 90 weeks. Continuous positive airway pressure therapy (CPAP) was initiated after 36±12 weeks. Change in Snellen and in logMAR visual acuity during the follow-up period was plotted over time to gauge the functional effect of anti-VEGF treatment. Anatomical effect of treatment was assessed using the Standardized Volumetric Change Index (SVCI) curve, which involves OCT thickness data normalized for the diurnal variation at each sector using an age-matched cohort. Using this curve, time-to-maximum effect of the anti-VEGF treatment, and time-to-anatomical stabilization were calculated.
Throughout the follow-up period: mean 81 weeks, patients received 10 ± 4 (6-14) bevacizumab injections.
Initial visual acuity (20/60 ± 20/16) decreased significantly despite therapy to reach a final visual acuity of 20/100 ± 20/32 at 82nd week.
The researchers concluded that untreated OSA hinders the response of wet AMD to pharmacotherapy with anti-VEGF. Treatment of OSA with CPAP yields a subsequent impressive anatomical response, however functional improvement does not follow. Identifying and treating underlying OSA earlier in the management of wet AMD may yield better functional outcomes.
|In the Subspecialty News section of the May issue of Retinal Physician, David Dodwell, MD, should have been credited as the first author of an ARVO study on repeated use of the Ozurdex implant. The ARVO presentation was the basis of a news article titled “Repeated Ozurdex Safe and Effective.” We regret the error.|
|■ Synergetics' USA portable vitrectomy machine is approved by the FDA. The VersaVIT, a lightweight, portable vitrectomy machine from Synergetics USA, has received 510(k) clearance from the FDA.|
VersaVIT, which was initially introduced at the 2011 AAO meeting, is the first product from Synergetics USA for the vitrectomy machine market and will extend the company's key ophthalmic product line into a market segment that currently generates $150 million in annual sales.
“We believe VersaVIT represents a new concept in retinal surgery with its highly portable design, moderate price and ease of use,” said David M. Hable, president and CEO of Synergetics USA. “It features a complete system in an under-25 pound package capable of running on battery power and gas cartridges, further enhancing its portability.”
The company notes that the small footprint of VersaVIT makes it ideally suited for use in ASCs, as a traveling unit for satellite offices and potentially for in-office procedures.
“The entry of VersaVIT into the global vitrectomy market is a major milestone in Synergetics' strategy to enter into higher growth areas of retinal surgery,” asserted Mr. Hable.
The company, based in O'Fallon, Mo., is awaiting CE mark approval, which has been submitted and is currently under review.
■ Drs. Boyer, Singerman to advise Ohr. Ohr Pharmaceutical Inc. has added David S. Boyer, MD, and Lawrence J. Singerman, MD, to its Scientific Advisory Board. The two retina specialists will assist in advancing OHR's squalamine eye drop program for retinal disease into clinical efficacy trials. They will advise the company on its clinical programs, regulatory strategy and provide strategic guidance for overall development.
“Ohr Pharmaceutical's squalamine eye drops, conveniently self-administered by the patient, could potentially provide great benefits to patients with wet AMD and other ophthalmological disorders,” said Dr. Singerman. RP