Clearside Meets Endpoints for Suprachoroidal Delivery

Gains of 15 letters or more in patients with uveitis.

■ Clearside Biomedical announced positive top-line results from its pivotal phase 3, 160-patient trial of suprachoroidal CLS-TA in patients with macular edema associated with noninfectious uveitis. CLS-TA is Clearside’s proprietary suspension of the corticosteroid triamcinolone acetonide formulated for administration to the back of the eye via the suprachoroidal space.

As Clearside CEO Daniel H. White noted during a conference call announcing the trial results, Clearside is unique in that it has exclusive rights to deliver drugs into the suprachoroidal space using its proprietary microinjector. Clearside believes the advantages of suprachoroidal delivery are the ability to target higher concentrations of drugs, fewer typical steroid side effects such as elevated IOP and cataract, and applicability to a wide range of eye diseases.

Of the 160 patients enrolled in the phase 3 PEACHTREE trial, 96 were randomized to the treatment arm to receive two 4.0-mg doses of suprachoroidal CLS-TA 12 weeks apart, and 64 were randomized to undergo sham procedures at the same 12-week interval. Patients were evaluated every 4 weeks for a total of 24 weeks, and a total of 155 patients, or 97% of those enrolled, completed the full evaluation period of the trial. In the PEACHTREE trial, 47% of patients who received suprachoroidal CLS-TA every 12 weeks gained at least 15 letters in BCVA, as measured using the ETDRS scale, from baseline to week 24, compared to 16% of patients who underwent a sham procedure (P<.001). The mean BCVA change from baseline was better in the treatment arm than the sham arm at each monthly evaluation. The mean improvement from baseline was maintained throughout the evaluation period, with 9.6 letters gained at week 4 and 13.7 letters at week 24 in the active arm, compared to 1.2 letters at week 4 and 2.9 letters at week 24 in the control arm, respectively.

In a key secondary endpoint, administration of suprachoroidal CLS-TA resulted in a mean reduction from baseline of 157 microns in central subfield thickness at week 24 in the active arm compared to a 19 micron mean reduction in the sham arm (P<.001). Subgroups of patients will be followed for 6 additional months to assess treatment durability.

Suprachoroidal CLS-TA was generally well tolerated, with no treatment-related serious adverse events reported in the trial. Through 24 weeks, corticosteroid-related elevated IOP adverse events were reported for approximately 11.5% of patients in the CLS-TA treatment group, compared to no patients in the sham group.

“The positive data reflect well on the suprachoroidal approach,” said investigator Rahul N. Khurana, MD, on the call held to discuss results. “The gain of 15 letters was the greatest proportional increase I’ve ever seen in a uveitis trial and CLS-TA resulted in lower increases in IOP than I’ve ever seen in my practice. The PEACHTREE study was the first pivotal phase 3 clinical trial of a drug candidate for patients with uveitic macular edema in which a BCVA measure was the primary efficacy endpoint, potentially raising the bar for future trials in this population.” Based on the positive results, and if marketing authorization is obtained from the FDA, said Dr. Khurana, suprachoroidal CLS-TA has the potential to become a new paradigm for treatment of visual impairment associated with macular edema associated with noninfectious uveitis.

“Having nearly 50% of the PEACHTREE trial patients treated with suprachoroidal CLS-TA gain 15 or more letters in vision is highly compelling,” said White in a press release. “It represents a huge step forward in advancing suprachoroidal administration of CLS-TA toward becoming a powerful new approach in potentially treating blinding eye diseases. We currently expect to submit a new drug application for suprachoroidal CLS-TA in patients with macular edema associated with uveitis to the FDA in the fourth quarter of 2018.”

Clearside’s stock price jumped approximately 60% when the shares opened for trading following the announcement of the trial results.

In other Clearside news, the company provided updates on 2 phase 3 trials in which suprachoroidal CLS-TA is being delivered in combination with an anti-VEGF agent to combat macular edema associated with RVO.

The company announced that the first patient has been enrolled in the TOPAZ study, which combines suprachoroidal CLS-TA with either Lucentis (Genentech) or Avastin (Genentech) in treatment-naïve patients. In addition, Clearside said that progress in patient enrollment will now allow preliminary data from the SAPPHIRE trial to be released in the fourth quarter of 2018 rather than the first quarter of 2019. In the SAPPHIRE trial, patients are being dosed with a combination of suprachoroidal CLS-TA and the anti-VEGF Eylea (Regeneron). If the primary endpoints are met in both the TOPAZ and SAPPHIRE trials, Clearside said it will seek an agnostic label to combine suprachoroidal CLS-TA with any anti-VEGF.

Duke to Study “Immunity Hormone” for GA

Alpha-MSH levels are key to clinical trial.

■ In a novel approach to combating retinal disease, the Duke University Eye Center has filed its intention to begin a 60-patient pilot clinical trial to collect information to ultimately determine if alpha-melanocyte stimulating hormone (alpha-MSH) of the melanocortin family of hormones can provide protection against geographic atrophy (GA) in eyes with dry age-related macular degeneration (AMD). Alpha-MSH plays a role in intraocular immune privilege and protects the retinal pigment epithelium cells from oxidative stress in animal studies. A small amount of aqueous humor (0.1 mL) will be drawn from 1 eye of each eligible patient and then assayed to determine the level of alpha-MSH.

Inclusion criteria for this study require that the individual be 60 years of age or older, have advanced dry AMD with foveal GA, have vision of 20/100 or worse, and be pseudophakic. Individuals in the trial must be pseudophakic because of the small chance of piercing the natural lens in a phakic eye when obtaining the aqueous study sample.

Lead investigator Sharon Fekrat, MD, FACS, professor of ophthalmology at the Duke Eye Center is collaborating with Avni Finn, MD, MBA, and Mohsin Ali, MD, at Duke as well as Andrew Taylor, PhD, at Boston University, who has been studying alpha-MSH for more than 2 decades.

“We will compare the levels of alpha-MSH in eyes with advanced dry AMD and foveal GA with the levels of alpha-MSH in a control group of eyes without AMD or uveitis undergoing cataract surgery,” Dr. Fekrat told Retinal Physician. “If levels in these dry AMD eyes are significantly lower, it may suggest that alpha-MSH plays a role in the development of GA and even dry AMD.”

Dr. Fekrat said that even though this study is diagnostic and nontherapeutic, it may have future therapeutic implications.

“If the dry AMD patients with foveal geographic atrophy are deficient in the alpha-MSH hormone compared to the normal control eyes, we may then look for ways to effectively replenish alpha-MSH levels in at-risk eyes, perhaps through a topical eye drop or intravitreal injection. We are approaching a common clinical scenario from a new angle, and eagerly await our results.”

Fellows Forum: Mentoring at Its Best

Dedicated faculty return year after year.

BY CARL AWH, MD

■ The 18th annual Retina Fellows’ Forum took place on January 26 and 27 at the Westin River North in Chicago. Seventy-five North American vitreoretinal fellows from more than 60 training programs participated in an educational and social program that has become a much-anticipated fixture of the final year of vitreoretinal training. Dedicated faculty members gave up a winter weekend — some for the 18^th consecutive year — to introduce fellows to current real-world issues of retina practice.

As in past years, the fellows spent considerable time in the lecture hall with a panel of faculty led by course director Tarek Hassan, MD, and co-directors Carl Awh, MD, and David Chow, MD. Drs. Dean Eliott, Mike Jumper, Peter Kaiser, Tamer Mahmoud, and Amy Schefler completed the faculty.

The meeting began on Friday with a session focused on controversies and current research in AMD. Lectures and discussion about current and future AMD research, intraocular tumors, and the latest retinal imaging technology rounded out the AMD session. The Friday evening reception and dinner provided the first opportunity for the graduating class of 2017 fellows to socialize with their peers, the faculty, and representatives from industry.

Saturday offered a full day of panel-driven discussions and one-on-one faculty debates. A highlight of the meeting was the Distinguished Guest Lecture, this year delivered by Gary Abrams, MD, on “Pivotal Moments in Vitreoretinal Surgery,” a reflection on his life and a career that seemed to intersect with every giant in our relatively young surgical discipline. The afternoon concluded with a “Real World” panel discussion devoted to career decisions, practice building, and balancing work and personal demands.

AI Studies Find Retina a Window Into Diseases

Everything from heart attack to memory loss.

■ Recent studies in the rapidly emerging field of artificial intelligence (AI) are finding that the human retina can provide a window into early detection of a wide range of diseases. Thus far, AI (also called machine learning) has proven accurate in such areas as retinal disease, heart attack, and memory loss.

One of the AI initiatives for early detection of retinal disease is the IDx-DR system, for which the FDA has granted “breakthrough device” status. IDx-DR uses AI to detect diabetic retinopathy (DR) automatically and is designed to be used during routine health-care visits. In a pivotal clinical trial of 900 patients with diabetes at 10 sites, the IDx-DR system exceeded performance goals developed in consultation with the FDA.

In March, Eyenuk, Inc. announced the publication of a study investigating its EyeArt screening software on retinal images acquired with the Remidio Fundus on Phone (FOP) system, an FDA 510k registered fundus camera that combines a smartphone with patented optics. The study demonstrated high sensitivity for detecting both any DR and sight-threatening DR, indicating potential for enabling highly sensitive yet cost-effective mass retinal screening.

In another study, led by researchers at Shiley Eye Institute at the University of San Diego School of Medicine and published in the journal Cell, researchers focused on macular degeneration and diabetic macular edema. Machine-derived diagnoses were compared with diagnoses from 5 ophthalmologists who reviewed the same scans. In addition to making a medical diagnosis, the AI platform also generated a referral and treatment recommendation not done in previous studies. The authors noted the machine performed similarly to a well-trained ophthalmologist, generating a decision on whether the patient should be referred for treatment within 30 seconds, with more than 95% accuracy.

In a study by Google, researchers fed retinal scans from more than 280,000 patients into its pattern-recognizing algorithms, known as neural networks. The scans train the networks on which tell-tale signs tended to indicate long-term health dangers. The study met with moderate success, recognizing 70% of the patients who had suffered a heart attack or stroke within the past 5 years.

Statins May Prevent Retinal Detachment Recurrence

Large study shows 28% risk reduction.

■ Statins may reduce the risk of repeated surgery in patients who undergo a vitrectomy for detached retina, Finnish researchers have found. The researchers believe that statins might prevent the formation of scar tissue inside the eye.

Conducted at the Helsinki University Central Hospital (HUCH), the study is based on data from a registry of Finnish patients who underwent vitreoretinal surgery. The study examined reintervention surgeries among 5,709 eye patients who were admitted to the hospital for a vitreoretinal surgical procedure between 2008 and 2014. The results indicate that use of statin medication at the time of surgery was associated with a 28% reduction in the risk of reintervention among patients who underwent a primary vitrectomy to treat retinal detachment. However, statin medication was not found to be associated with a reduced risk of renewed surgery in the other vitreoretinal disease groups involving retinal surgery, such as age-related macular pucker formation, or vitrectomies performed to treat diabetic retinopathy.

The researchers believe that the benefits of statin medication on retinal detachment patients is probably due to the statin reducing the inflammation inside the eye and hindering the formation of scar tissue.

“Our previous work has indicated that the amount of biochemical markers related to the scar tissue formation is lower in the vitreous gel of subjects receiving statin medication than it is in the vitreous gel of control subjects without statin, and therefore, we considered it necessary to investigate further,” said Docent Sirpa Loukovaara of the HUCH eye clinic, in a news release.

Researchers at Mass Eye and Ear have also reported promising early results in the use of high-dose statins to combat dry AMD. The statins appear to clear lipid debris, which improves visual acuity and retards disease progression.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Next-generation Quantel Medical ultrasound approved

■ Quantel Medical has received approval from the FDA for the next-generation Compact Touch ophthalmic ultrasound platform. Improvements in the new generation of Compact Touch include a 15 MHz B probe to increase the quality of the B-scan imaging essential to vitreoretinal specialists. Interactivity is enhanced with DICOM compatibility, WiFi and Bluetooth connectivity, and HDMI video output. The modern design now utilizes a new-generation touchscreen interface, and the device is as silent as a tablet. Quantel Medical points to user-friendly design and software enhancements that improve workflow.

Since the first generation of Compact Touch was launched in 2008, more than 3,300 units have been sold worldwide. Quantel Medical says the Compact Touch has been prized for its high image quality, intuitive software, compact design, and versatility.

Apellis GA drug has residual effectiveness

■ Apellis said its APL-2 complement inhibitor demonstrated residual effectiveness in combating lesion progression in geographic atrophy even 6 months after treatment ended. This finding was revealed in recently released 18-month data for the company’s phase 2 FILLY trial.

Previously, the company had released 12-month data for the FILLY trial, which covered the active treatment period. At 12 months, patients treated monthly averaged 29% less lesion progression compared to sham, while those treated every other month averaged 20% less. At 18 months, those who had previously been treated monthly averaged 12% less lesion progression than sham over the nontreatment period and those treated every other month averaged 9% less progression over the same period. These findings indicate that regular dosing of APL-2 will be required to achieve maximum effectiveness.

Opthea begins new studies for wet AMD and DME

■ Building on highly promising early-stage results for its anti-VEGF drug OPT-302, which combats VEGF-C and -D, Opthea has begun 2 new clinical trials in wet AMD and DME. The new studies consist of a 350-patient phase 2b trial in combination with Lucentis for treatment-naïve wet AMD patients begun in December and a 117-patient phase 2a trial in combination with Eylea for patients with DME begun in January.

Ophthotech begins gene therapy collaboration

■ Ophthotech Corporation announced that the company has initiated an innovative gene-therapy research collaboration focused on applying novel gene therapy technology to discover and develop next-generation therapies for the treatment of ocular diseases. As part of Ophthotech’s strategy, the company has entered into a series of sponsored research agreements with the University of Massachusetts Medical School and its Horae Gene Therapy Center to utilize their “minigene” therapy approach and other novel gene delivery technologies to target retinal diseases.

Natural history of AMD to be studied

■ A new clinical study led by the National Eye Institute (NEI), part of the National Institutes of Health, will follow 500 people over 5 years to learn more about the natural history of early age-related macular degeneration. By using the latest technologies to visualize structures within the eye and measure their function, researchers hope to identify biomarkers of disease progression, well before it advances to late-stage disease and causes vision loss.

“The findings will contribute to our understanding of the underlying biology driving the transition from early- to late-stage disease so that therapies can be developed to halt its progression,” said the study’s lead investigator, Emily Y. Chew, MD, deputy clinical director at NEI and director of the NEI Division of Epidemiology and Clinical Applications. “Treatments that halt the disease at its early stage would have an enormous public health impact.”

Santen wet AMD drug in early-stage trial

■ Santen presented encouraging data in combating refractory wet AMD in a 12-patient, phase 1/2 clinical trial for its novel protein-inhibiting antibody carotuximab (DE-122) at the Angiogenesis 2018 conference in Miami. Santen says the drug, which acts against the protein endoglin, is intended to optimize the efficacy of anti-VEGF agents and is already in a phase 2a trial in combination with Lucentis.

The drug, delivered via intravitreal injection at 4 different dose levels (3 patients at each dose), was reported to be well tolerated while displaying positive biological activity as measured by mean change in central subfield thickness.

Plasma kallikrein inhibitors for DME

■ KalVista Pharmaceuticals, a clinical-stage pharmaceutical company focused on the development of small molecule protease inhibitors, in collaboration with Merchas initiated a phase 2 proof-of-concept clinical trial evaluating the safety, tolerability, and efficacy of the plasma kallikrein inhibitor KVD001 as a treatment for DME.

“We are particularly hopeful that plasma kallikrein inhibition may offer benefits in patients for whom anti-VEGF therapy doesn’t achieve a sufficient response,” said Andrew Crockett, CEO of KalVista.

KVD001 is a small-molecule plasma kallikrein inhibitor administered by intravitreal injection. The phase 2 trial will consist of approximately 123 patients in the United States who have discontinued treatment with anti-VEGF therapy, and who still have significant edema and reduced visual acuity. Top-line results are expected in the second half of 2019.

Another company, AntriaBio (recent name change to Rezolute), has announced its intention to soon begin a clinical trial in DME for its oral plasma kallikrein inhibitor AB402.

Follow-up needed after retinal infarction

■ Not enough patients with retinal infarction are evaluated for stroke risk or seen by a neurologist, putting them at increased risk for another stroke, according to preliminary research presented at the American Stroke Association’s International Stroke Conference 2018.

The study showed that 1 in 100 patients in the study experienced an ischemic stroke within 90 days of a retinal infarction. In addition, among 5,688 individuals with retinal infarction, only one-third underwent basic testing, and fewer than 1 in 10 were seen by a neurologist. Within 90 days of symptoms, only 34% received cervical carotid imaging tests; 28.6% received heart-rhythm testing; 23.3% received echocardiography; and 8.4% were evaluated by a neurologist. The findings illustrate the importance of expediting stroke evaluation testing for those who have experienced a retinal infarction, and for increased awareness and understanding about retinal infarctions and how they may signal future strokes.

Regeneron recalls syringes linked to ocular inflammation

■ Regeneron has recalled a batch of syringes included in some Eylea kits and that have been linked to some incidents of intraocular inflammation. In a letter to US doctors, Regeneron said it would exchange the syringes for new ones.

The Assistance Fund to help IRD patients

■ The Assistance Fund, an Orlando-based independent charitable patient assistance foundation, said it will now offer financial support to defray patients’ medical and insurance costs associated with inherited retinal diseases. Formed in 2009, the Assistance Fund says it has helped more than 43,000 adults and children access the medicines they need to maintain health or manage a chronic condition. For more information, visit www.tafcares.org .

New informational website on retinal disease

■ Regeneron has launched an educational and informational website for patients with retinal disease and their caregivers. The site — LooktoYourFuture.com — provides numerous resources that can be accessed for a wide range of information on living with retinal disease. This includes questions patients can ask their doctors and a video series featuring noted retina specialists Drs. David Brown and Andrew Moshfeghi.

Largest Bascom Palmer gift targets retinal diseases

■ Lois Pope, whose mother went blind from macular degeneration, is donating $12 million to the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine to establish a home for collaborative, cutting-edge macular degeneration and retinal diseases research and to create a clinical research endowment. The gift from Mrs. Pope is the largest single donation that Bascom Palmer, the nation’s top-ranked ophthalmology program, has received in its 56-year history. To honor her generosity, Bascom Palmer will establish the Lois Pope Center for Retinal & Macular Degeneration Research located on the Institute’s Palm Beach Gardens campus.

Second Sight does first Argus implant in Singapore

■ Second Sight Medical Products, a developer, manufacturer and marketer of implantable visual prosthetics that are intended to create an artificial form of useful vision for blind patients, has announced market entry into Singapore, with the first patient implanted with the company’s Argus II Retinal Prosthesis System. The implantation in a 62-year-old male with retinal degeneration was facilitated by the company’s exclusive distribution partner in Singapore, Mandarin Opto-Medic Co Pte Ltd.