Dry AMD Highlights From Angiogenesis
Efforts continue to combat a challenging disease.
BY REHAN M. HUSSAIN, MD
■ New data on AMD and related therapies were presented in February at the Angiogenesis meeting held by the Bascom Palmer Eye Institute in Miami, Florida. One important presentation was by Nancy Holekamp, MD, on the Proxima A and B trials. These 2 large prospective observational studies demonstrated the severe functional impact of GA and rapid rate of GA lesion progression over 2 years. The GA lesion size increased by 2.1 mm2 and 1.8 mm2 by 12 months in Proxima A, and 4 mm2 and 3.5 mm2 by 24 months in Proxima B. Patients lost about 5 ETDRS letters at 1 year and 10 ETDRS letters by 2 years across all subgroups. “This lies contrary to the perception that GA is a slowly progressive disease,” concluded Dr. Holekamp.
Jeffrey Heier, MD, presented new data from year 1 of the 2-year PRO-CON study. PRO-CON is a prospective, single-blind, randomized study investigating prophylactic quarterly intravitreal aflibercept (Eylea; Regeneron) injection to prevent conversion to wet AMD in 128 high-risk dry AMD eyes (defined as intermediate AMD in the study eye and wet AMD in the fellow eye). The interim analysis at 12 months did not demonstrate any statistically significant benefit of intravitreal aflibercept compared to sham, with a conversion rate of 6.4% in the intravitreal aflibercept group and 9.4% in the sham group (P=.76).
Jay Duker, MD, presented phase 1 results of HMR59 (Hemera Biosciences) to treat dry AMD with GA. HMR59 is an adeno-associated virus gene therapy that is delivered as a one-time intravitreal injection. The transgene product is soluble CD59, which blocks complement at the membrane attack complex. HMR59 was generally well tolerated, although 3 of 17 subjects (18%) developed mild vitritis that was responsive to topical steroids. There was a 23% reduction in GA growth at the highest dose compared to historical controls (1.82 mm2 vs 2.36 mm2), and no HMR59-treated eyes converted to wet AMD during 18-month follow-up.
Rehan M. Hussain, MD, is a vitreoretinal surgery fellow at the Bascom Palmer Eye Institute in Miami, Florida.
Elevated IOP After Anti-VEGF Injection
A prolonged rise is cause for concern.
BY JERRY HELZNER, CONTRIBUTING EDITOR
■ Researchers led by Ambika Hoguet, MD, of Ophthalmic Consultants of Boston, assessed the effect of intravitreal injections of anti-VEGF agents on immediate and long-term intraocular pressure (IOP) elevation and glaucoma. Their findings were recently reported in the journal Ophthalmology.
Literature searches of the PubMed and Cochrane databases, last conducted in April 2018, yielded 34 usable related studies. The studies that reported on short-term IOP elevation (ie, between 0 and 60 minutes) showed that an immediate increase in IOP is seen in all patients when measured between 0 and 30 minutes of intravitreal injection and that IOP elevation decreases over time. The data on long-term IOP elevation were mixed; 7 studies reported that between 4% and 15% of patients developed sustained IOP elevation at 9 to 24 months after injection, whereas 6 studies found no long-term change in IOP from 1 to 36 months after injection.
Pretreatment with glaucoma medications, anterior chamber tap, vitreous reflux, longer intervals between injections, and longer axial lengths were associated with lower IOP elevations after injection. Data were mixed on the relationship between IOP rise and type of intravitreal injection, number of intravitreal injections, pre-existing glaucoma, and globe decompression before injection. There were no data on the onset or progression of glaucoma in the studies reviewed in this assessment.
The researchers found that intravitreal injection of anti-VEGF agents results in an immediate and transient rise in IOP. A long-term increase in IOP may be seen as well, and further studies are needed to determine at-risk populations. Although there is some suggestion in the literature, there are insufficient data to determine the impact of intravitreal anti-VEGF injections on glaucoma progression. The clinical significance and associated risks are unknown for interventions such as pretreatment with glaucoma medications, performing anterior-chamber paracentesis, or increasing the interval between intravitreal injections, although they may reduce the impact of transient IOP elevation.
Plasma Kallikrein Inhibition Targets Chronic DME
KalVista advances clinical studies to phase 2.
■ After more than a decade of preclinical research, initiated and primarily conducted at the Joslin Diabetes Center and Harvard Medical School, a potentially transformative therapy for DME not responsive to anti-VEGF has advanced into human clinical trials. Researchers at Joslin identified high levels of the enzyme plasma kallikrein (PKal) in the vitreous from DME patients and performed preclinical studies demonstrating that PKal increases retinal vascular permeability and edema. In a 14-patient open-label phase 1b study undertaken by KalVista Pharmaceuticals, the effects of intravitreal injection of the company’s small-molecule PKal inhibitor KVD001 in DME patients were investigated. This first-in-human study showed that KVD001 was generally well tolerated. Although this was not an efficacy study, most subjects showed improvement in BCVA and reduced central subfield thickness (CST).
KalVista, in collaboration with partner Merck, has since advanced its PKal program to a 123-patient phase 2 study, with completion anticipated in the second half of 2019. The phase 2 trial consists of patients in the United States who have discontinued treatment with anti-VEGF therapy and who still have significant edema and reduced visual acuity. This sham-controlled, double-masked clinical trial will evaluate 2 dose levels of KVD001. Four intravitreal injections, or sham, will be administered over 3 months with a 3-month follow-up period. Efficacy endpoints include best-corrected visual acuity, CST, and the diabetic retinopathy severity scale. The safety and tolerability of monthly dosing of KVD001 will also be assessed.
KalVista Chief Scientific Officer Edward Feener, PhD, formerly a senior investigator at Joslin, told Retinal Physician that preclinical studies show that PKal inhibition blocks both VEGF-dependent and VEGF-independent retinal edema, suggesting that this approach might be useful in treating a range of retinal diseases. He leaves the door open for potential combination therapies that include a PKal inhibitor and another drug. KalVista is also developing oral PKal inhibitors for DME and hereditary angioedema.
While KalVista has the most advanced clinical program in PKal inhibition, 2 other companies, ThromboGenics NV (now Oxurion) and Rezolute (formerly AntriaBio) are currently pursuing the same target.
Intravitreal Pan-VEGF Inhibitor Effective in Wet AMD Trial
Positive topline results announced for the ADAGIO phase 1/2a study.
■ Graybug Vision has announced positive topline results for the ADAGIO study, a phase 1/2a study of intravitreal GB-102 (sunitinib malate) in patients with wet AMD. Overall, 88% and 68% of evaluable patients were maintained on only a single dose of GB-102 at 3 and 6 months, respectively. GB-102 is a depot formulation of sunitinib malate intended for intravitreal (IVT) injection. Sunitinib malate is an inhibitor of VEGFR-1, -2, and -3, receptors known to play an influential role in the development and progression of wet AMD.
ADAGIO met the primary endpoints of safety and tolerability without dose-limiting toxicities, drug-related serious adverse events, or inflammation. Secondary outcomes demonstrated evidence of stability and maintenance of visual acuity and central retinal thickness that was durable over at least 6 months as measured by eye chart readings and optical coherence tomography (OCT). The OCT measurements showed statistically significant maintenance of reduction in the central subfield thickness at all monthly visits compared to historical pre-GB-102 measures. Rescue treatment was available for those patients who met criteria.
“We are very encouraged with results obtained from our clinical study of GB-102,” said Jerry Cagle, PhD, acting CEO of Graybug Vision, in a news release. “In our ADAGIO study, GB-102 demonstrated safety and efficacy, with a duration of effect reaching 6-8 months from a single intravitreal injection.”
The ADAGIO clinical trial was an open-label, single-dose study that enrolled 32 patients from 8 centers located in the United States. Patients enrolled in the study were previously treated with at least 3 prior intravitreal injections of any anti-VEGF agent current standard of care treatment and had to demonstrate a response to anti-VEGF treatment.
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
Kodiak Sciences Anti-VEGF Has 12-Week Durability in DME
■ Kodiak Sciences reported encouraging 12-week data from its phase 1a single ascending-dose clinical study of KSI-301, an investigational anti-VEGF antibody biopolymer conjugate, in 9 patients with severe DME. KSI-301 is now poised for rapid development over a range of retinal diseases, according to the company.
After 1 dose, 8 of 9 patients responded to KSI-301, as assessed by improvement from baseline in vision, anatomy, or both. Rapid improvements were observed as early as 1 week after the injection. The treatment effect increased through 4 weeks, resulting in a median best-corrected visual acuity (BCVA) improvement of 12.5 eye-chart letters and median central retinal thickness on OCT improvement of 120 microns, pooled across all 3 dose levels.
Among the responders to KSI-301, all had sustained improvements from baseline (vision, retinal anatomy, or both) at the 12-week last visit. At 12 weeks after the single dose, a median BCVA improvement of 9 eye-chart letters and median OCT improvement of 121 microns were observed, pooled across all 3 dose levels.
Through the 12-week last visit, single doses of KSI-301 demonstrated no dose-limiting toxicities, no drug-related adverse events, and no signs of intraocular inflammation. The highest dose tested, 5 mg, has been selected for advancement into pivotal studies.
“We are very encouraged by the depth and durability of treatment responses. This study of KSI-301 was designed as a first-in-human, single-dose safety study and has exceeded our expectations from the standpoints of bioactivity and durability,” said Jason Ehrlich, MD, PhD, Kodiak’s chief medical officer and chief development officer, in a company news release. “Our phase 1b multiple-dose study is now recruiting patients with neovascular age-related macular degeneration, DME, and macular edema due to retinal vein occlusion. Given the results of the phase 1a study, we are excited about the potential for important durability signals to emerge in phase 1b.”
EyePoint Launches Yutiq 3-Year Uveitis Implant
■ EyePoint Pharmaceuticals has announced the US launch of Yutiq, an FDA-approved, 3-year microinsert for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. The product is now available for ordering and delivery to physicians.
“We are pleased to announce the availability of Yutiq in the US, an advancement in the treatment of chronic, noninfectious posterior segment uveitis,” said Nancy Lurker, president and CEO of EyePoint Pharmaceuticals, in a news release. “Yutiq is the first FDA-approved fluocinolone acetonide microinsert to address this serious condition that is the third leading cause of blindness in the country.
One Yutiq microinsert can deliver up to 3 years of fluocinolone acetonide, a commonly used steroid, with continuous dosing that avoids the peaks and valleys of local corticosteroids, the current standard of care. In clinical studies, Yutiq significantly reduced the number of inflammatory uveitis eye flares, which can lead to blindness.”
Statins Lower Risk for Diabetic Retinopathy
■ In a large-scale, 15-year retrospective study of 37,894 Taiwanese patients with type 2 diabetes and dyslipidemia, those taking statins had a significantly lower rate of diabetic retinopathy (10.6% vs 12.0%). Statin therapy was also associated with lower risks of major adverse cardiovascular events, new-onset diabetic neuropathy, and new-onset diabetic foot ulcers. The research was reported in JAMA Ophthalmology.
Pneumatic Retinopexy Seen Superior for Retinal Detachment
■ Minimally invasive and less expensive pneumatic retinopexy (PnR) for simple retinal detachment gives most patients sharper vision, less distortion, and reduced side effects, according to the findings of a randomized controlled trial performed at St. Michael’s Hospital in Toronto. The findings were published in the journal Ophthalmology.
“The most commonly offered treatment for a retinal detachment in North America is vitrectomy (PPV) in the OR. The results of this study clearly demonstrate that many retinal detachments will have better results for patients with an alternative minimally invasive office procedure,” said co-principal investigator Rajeev H. Muni, MD, a vitreoretinal surgeon at St. Michael’s, in a news release.
The trial involved 176 patients who were randomly assigned to either PnR or PPV after being diagnosed with a retinal detachment. The primary outcome being researched was visual acuity 1 year after treatment, as well as a metamorphopsia score for visual distortion and anatomical success.
Patients who underwent PnR scored an average of 4.9 letters better on a standardized visual acuity test compared to those who had PPV and had less visual distortion. A greater proportion of patients who had PnR achieved driving vision (20/40) in the affected eye than those who had PPV (90.3% vs 75.3%). Although patients who had PPV treatment did have higher rates of primary anatomical success than those who had PnR (93.2% vs 80.8%), patients who failed PnR still had very good visual outcomes, with secondary anatomical success being virtually identical between the groups. Patients in the PnR group also reported quicker recoveries and better quality of life in the 6 months after being treated.
Vision Gains Comparable in Treat-and-Extend Study
■ Australian researchers have reported interim 1-year data for the planned 2-year treat-and-extend RIVAL study comparing vision gains achieved by ranibizumab (Lucentis; Genentech) and aflibercept (Eylea; Regeneron) in a cohort of 278 treatment-naïve patients with wet AMD. Although ranibizumab produced a larger mean change of +7.2 letters compared to the +4.9-letter gain achieved by aflibercept, the researchers concluded that neither anti-VEGF was superior to the other in terms of BCVA gains and number of injections in year 1 of the treat-and-extend study. Further analysis will be conducted when 2-year data becomes available. The mean number of injections for both drugs was 9.7 over the first 12 months of the study, which was reported in JAMA Ophthalmology.
Tolerating Subretinal Fluid in a Treat-and-Extend Regimen
■ Researchers led by Robyn H. Guymer, MBBS, PhD, of the University of Melbourne in Australia, conducted a 24-month, 279-patient study to test the hypothesis that tolerating some subretinal fluid (SRF) in patients with wet AMD treated with ranibizumab (Lucentis; Genentech) using a treat-and-extend regimen can achieve similar visual acuity outcomes as treatment aimed at resolving all SRF. Subjects with active subfoveal choroidal neovascularization (CNV) were randomized to receive ranibizumab 0.5 mg monthly until either complete resolution of SRF and intraretinal fluid (IRF) (intensive arm: SRF intolerant) or resolution of all IRF only (relaxed arm: SRF tolerant except for SRF >200 μm at the foveal center) before extending treatment intervals. A 5-letter noninferiority margin was applied to the primary outcome measure.
The mean change in BCVA from baseline to month 24 was +16.3 letters in the intensive group and +16.3 letters in the relaxed group, demonstrating noninferiority of the relaxed to the intensive treatment. Similar proportions of the intensive and relaxed groups achieved ≥20/40 VA (53.5% and 56.6%, respectively) and ≤20/200 VA (8.7% and 8.1%, respectively).
Results were supported by the per-protocol analysis and with adjustment for confounding baseline factors. Subjects in the relaxed group received fewer ranibizumab injections over 24 months (mean 15.8) than those in the intensive group (mean 17). Significantly more subjects in the intensive group never extended beyond 4-week treatment intervals (13.5%) than in the relaxed group (2.8%) and significantly more subjects in the relaxed group extended to and maintained 12-weekly treatment intervals (29.6%) than the intensive group (15.0%).
Study Measures Progression of Small Melanoma
■ Researchers led by Carol Shields, MD, of Wills Eye Hospital, set out to analyze outcomes of plaque radiotherapy for small choroidal melanoma 3 mm in thickness or less in a retrospective study of 1,780 patients.
The researchers examined the patients for progression at 1, 5, and 10 years. They found that small choroidal melanoma treated with plaque radiotherapy has a 10-year risk for visual acuity loss of 48.9% and a 10-year risk of systemic metastasis of 8.8%. In this analysis, each millimeter of increasing thickness and diameter contributed risk for metastatic disease.
Clinical features predictive of melanoma-associated metastasis included increasing patient age, tumor diameter, tumor thickness, photopsia symptoms, and prior treatment before plaque radiotherapy. The study appeared in the journal JAMA Ophthalmology.
Drs. High and Bennett Win $1 Million Innovation Award
■ South Dakota-based Sanford Health has named 2 researchers whose groundbreaking work in gene therapy reversed the vision-robbing effects of an inherited retinal disease as the winners of its first $1 million Lorraine Cross award. Jean Bennett, MD, PhD, and Katherine A. High, MD, were honored for their work in correcting the blindness caused by the RPE65 mutation.
Drs. Bennett and High pioneered the gene therapy, took it to clinical trials under the sponsorship of Spark Therapeutics and then received FDA approval for the treatment, the first FDA approval of a gene therapy for a genetic disease. Dr. High also co-founded Spark Therapeutics, now a fully integrated, commercial gene therapy company dedicated to bringing new gene therapies to market. Dr. Bennett is a professor of ophthalmology at the University of Pennsylvania and Dr. High is president and head of research and development at Spark Therapeutics.
Ionis to Collaborate With Roche on GA Drug
■ Ionis Pharmaceuticals has announced a new collaboration with Roche to develop IONIS-FB-LRx for the treatment of complement-mediated diseases. The first indication the 2 companies will pursue is geographic atrophy (GA). A phase 2 study in patients with GA is planned to begin in early 2019.
IONIS-FB-LRx is an antisense drug using Ionis’s ligand conjugated antisense (LICA) technology. It reduces the production of FB, a key protein in the complement innate immune system. FB is predominately produced in the liver and circulates throughout the vascular system, including vessels in the eye and kidney. This complement protein plays a pivotal role in an innate immunogenic cascade that, when overactivated, has been associated with the development of several complement-mediated diseases, including dry AMD. In a phase 1 study in 54 healthy volunteers, IONIS-FB-LRx reduced plasma FB and was safe and well tolerated.
Under this new collaboration with Roche, Ionis will receive a $75 million upfront payment. In addition, Ionis is eligible to receive up to $684 million in development, regulatory, and sales milestone payments and license fees.
Alcon Launches Training Program for Retina Fellows
■ Alcon has begun a new and comprehensive training opportunity for retina fellows, the Alcon Retina Fellows Institute. The inaugural weekend-long program, which took place late last year in Fort Worth, Texas, invited 40 fellows to enhance their education through experiential surgical trainings.
This hands-on program emphasizes well-rounded learning over lecturing by featuring the latest innovations in retina surgery, led by a small group of world-class faculty. The program will take place annually.
The innovative training program aims to create well-rounded fellows by bridging gaps in education and experience with hands-on training for key procedures in a surgical laboratory setting. The program is split into a variety of segments, during which participants rotate through a schedule of lessons ranging from fluidics and sutureless intraocular lenses, to the ergonomics of operating room setup and independent surgery. Each fellow is offered the chance to actively learn the latest techniques in face-to-face training with highly experienced retina specialists.
FDA Plans New Standards for Medical Devices
■ The FDA said it will revamp a longstanding approval system for medical devices that primarily relies on comparison with existing devices. The system has been sharply criticized for failing to fully take into account new technologies and clinical trials. The current approval standards, which have been in use for decades, generally allow manufacturers to introduce new products based on similarities to already approved devices.
A new study of medical device safety initiated by the International Consortium of Investigative Journalists found that, over 10 years, reports of product defects link more than 1.7 million injuries and nearly 83,000 deaths to medical devices.
“We believe that newer devices should be compared to the benefits and risks of more modern technology,” said FDA Commissioner Scott Gottlieb in a statement. Gottlieb said the changes being proposed, some of which may take years to implement, would require companies to compare their devices to current technology rather than rely on comparisons to older products.
AGTC Gene Therapy Shows No Clinical Activity
■ Gene-therapy company AGTC reported topline interim 6-month data from its phase 1/2 clinical trial of its investigational AAV-based gene therapy delivered via intravitreal injection for X-linked retinoschisis (XLRS) due to mutations in the RS1 gene. Results from the study show the therapy is generally safe and well tolerated, but no signs of clinical activity were observed at 6 months.
AGTC also announced that the company will regain full rights to the XLRS and X-linked retinitis pigmentosa (XLRP) programs and the 3 other partnered discovery programs following Biogen’s termination of their collaboration agreement.
Aerie to Initiate Study of Dexamethasone Implant
■ Aerie Pharmaceuticals said the FDA has reviewed the Investigational New Drug (IND) application for AR-1105 (dexamethasone intravitreal implant) and it is now in effect, allowing Aerie to initiate human studies in the treatment of macular edema due to RVO. The IND was submitted in December 2018. Aerie expects to initiate a phase 2 clinical study in the near future.
AR-1105 is a bioerodible implant designed to release the steroid dexamethasone in a sustained fashion for 6 months. The device is delivered by intravitreal injection. The potential benefits of AR-1105 compared to other steroid products include 6-month duration of efficacy, improved administration due to a smaller needle size, and possibly a better safety profile due to lower peak drug levels.
Pixium Vision System Shows Promise in Advanced Dry AMD
■ The French bioelectronics company Pixium Vision has reported that its Prima Bionic Vision System has restored some central vision in patients with advanced dry AMD who were participating in a clinical feasibility trial. At 6 months, a majority of patients, all of whom had no central vision upon trial enrollment, were able to identify complex patterns, numbers, or letters. Their speed and accuracy in identifying the visual information improved with rehabilitation. The system was safe and well tolerated. Pixium Vision also reported that visual acuity for patients in the study measured up to 20/460, which is the highest visual acuity published to date for current retinal bionic or prosthetic technologies. RP