Urgent Cases Diagnosed by Telemedicine

Comparing virtual exams to in-person findings.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ Although telemedicine has proven itself a valuable screening tool, it has little history in playing a role in actual, real-time diagnoses. To that end, Massachusetts Eye and Ear Infirmary conducted an experiment in which 45 patients (mean age 54.8) who arrived at the emergency room with “urgent” ophthalmic complaints were evaluated by both traditional “hands-on” examinations and remotely by a panel of 3 staff physicians using only a patient questionnaire, anterior and posterior segment photos, and a set of ophthalmic vital signs.

The remote findings were then compared to in-person clinical findings. Primary outcomes included the consensus on triage status and diagnosis between virtual and live examination, as well as the degree of agreement among virtual examiners’ triage statuses and diagnoses. The confidence level of the virtual examiners for their exam was also measured. Findings were presented at the recent ARVO 2017 meeting.

Using the in-person exam as the benchmark, 5 patients were incorrectly triaged as nonurgent by teleophthalmology and 1 patient was incorrectly triaged as urgent relative to the live reference standard. Of the 45 patients in the pilot, 33.3% did not demonstrate agreement on diagnosis. However, 10 out of 15 (66.6%) of these patients did have a correct triage status despite the incorrect virtual diagnosis.

The average confidence for all examinations was 5.85 (out of 10), with an average confidence of 6.03 for correct triage, 4.72 for incorrect triage, 6.38 for correct diagnoses, and 4.80 for incorrect diagnoses.

The researchers, led by John L. Romano, MD, concluded that a teleophthalmic approach may reliably triage patients with urgent complaints, but is less reliable for diagnosis. They found that a larger study is needed to establish significance and to determine subgroups of chief complaint or presenting symptoms for which the protocol can be used with high sensitivity.

Genetic Exploration at ARVO

Retina researchers open the door to potential therapies for retinal disease.

BY LOUISE GAGNON, CONTRIBUTING WRITER

■ BALTIMORE, MD – At this year’s ARVO meeting, leading investigators pointed to several genes or gene variants linked to conditions like AMD and described how the identification of these gene variants produces novel targets for potential therapeutic candidates.

Indeed, genetic discoveries are providing insight into new disease mechanisms, and new therapies may emerge from these discoveries, according to Johanna M. Seddon MD, ScM, a retina specialist and genetic epidemiologist at New England Eye Center, the recipient of the 2017 Mildred Weisenfeld Award for Excellence in Ophthalmology given at this year’s annual ARVO meeting. Dr. Seddon is professor of ophthalmology at Tufts University School of Medicine and founding director of the Ophthalmic Epidemiology and Genetics Service of Tufts Medical Center in Boston, Massachusetts.

“I think we are heading toward precision medicine and stratifying patients into different genetic risk groups to deliver treatments based on genetic susceptibilities,” said Dr. Seddon in her address at ARVO’s annual meeting this year, citing the regeneration of cells in the retina as an emerging therapy that holds promise for degenerative retinal diseases.

Epigenetics is also a focus of research, and its importance is underscored by occurrences such as homozygotic twins discordant for severity of AMD, according to Dr. Seddon. Some individuals, based on their genetic profile, experience greater gains in terms of protection from GA through dietary modification such as consumption of folate, illustrating epigenetics at work, she said.

Another gene variant that appears to play a role in diseases like AMD is complement factor I. “When complement factor I is not working well, you have presumably more inflammation and greater risk of AMD,” said Teri Manolio MD, PhD, director of the Division of Genomic Medicine at the National Human Genome Research Institute in Bethesda, Maryland, speaking as a panelist at ARVO’s annual meeting closing keynote on the genetics of AMD.

Therapies can be developed that aim to replicate the function of complement factor I, explained Dr. Manolio. “If you can find a way of increasing the function (of complement factor I) with a drug, that might be a (therapeutic) possibility,” she said in an interview with Retinal Physician.

Dr. Maniolo added that there are also examples in other fields of genetic variants conferring protection, such as in the cardiology space. PCSK9 inhibitors were developed that are now being prescribed as cholesterol-lowering drugs. Large-scale reference databases and functional assays will be instrumental to developing therapies for ophthalmologic conditions, she said.

Still another gene that has been found to affect numerous ophthalmologic conditions is GRIK5, noted Nancy J. Cox, PhD, director of the Vanderbilt Genetics Institute and the Division of Genetic Medicine and professor at Vanderbilt University School of Medicine in Nashville, Tennessee. Reduced expression of the gene is associated with many eye phenotypes, she said.

“We intend to keep following this gene,” said Dr. Cox, adding that the challenge for developing possible therapies is to find avenues to upregulate the gene. “It’s usually easier to upregulate a gene or gene protein than to downregulate it,” she told Retinal Physician.

Study: Endophthalmitis After Intravitreal Injection

Worst outcomes associated with Streptococcus organisms.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ Researchers at Bascom Palmer Eye Institute conducted a major retrospective review of 38 cases of endophthalmitis that presented in the 4 weeks following intravitreal injection over the decade from 2006 to 2015. A key conclusion was that the worst visual outcomes were associated with Streptococcus organisms. The complete findings were presented at the recent ARVO 2017 meeting.

Of the 38 cases reviewed, 27 were referrals and 11 were in-house. The most common reason for treatment was wet AMD in 30 of 38 (79%) eyes. The therapies used were bevacizumab in 24 of 38 (63%), ranibizumab in 8 (21%), and aflibercept in 3 (8%) eyes. The mean time between injection and diagnosis of endophthalmitis was 4 days. Hypopyon was present in 26 of 38 (68%) and fibrin in 18 (47%) eyes.

Following the diagnosis of endophthalmitis, initial treatment included intravitreal vancomycin and ceftazidime in 37 of 38 (97%) and intravitreal vancomycin and amikacin in 1 (3%) eye. Intravitreal dexamethasone was used in 26 of 38 (68%) eyes. A vitreous tap and injection with antibiotics was performed as part of the initial treatment in 37 of 38 (97%) and pars plana vitrectomy in 1 (3%) eye.

Coagulase-negative Staphylococcus was isolated in 18 of 38 (47%), Streptococcus species in 14 (37%), Staphylococcus warneri in 3 (8%) eyes, and Staphylococcus aureus, Bacillus, and Haemophilus Influenzae each in 1 (3%) eye. None of the gram-positive isolates were vancomycin resistant.

A visual acuity of ≥20/40 was achieved in 4 of 38 (11%) eyes and ≥5/200 in 21 (55%) eyes. Ten of 38 (26%) eyes were no light perception at last follow-up, and all of these eyes had Streptococcus species.

The researchers concluded that most common causative organisms in post-intravitreal injection endophthalmitis are gram positive. In this study, there were no vancomycin-resistant gram-positive isolates. Visual outcomes were generally poor and the worst outcomes were Streptococcus cases.

Neuroprotectives Are New Focus for GA

Brimonidine implant is showing promise.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ If the key to meeting the currently unmet medical need of successfully treating GA is to halt the process of photoreceptor cell death, then it stands to reason that neuroprotective therapies could play a leading role in combating the disease.

That’s why leading retina researchers such as Joan Miller, MD, of Harvard, David Zacks, MD, PhD, of ONL Therapeutics and the Kellogg Eye Center, University of Michigan, Baruch Kuppermann, MD, of UC Irvine, and Anthony Adamis, MD, of Genentech are showing increasing interest in developing neuroprotectives for GA. Currently, there are several drug development initiatives — either now in clinical trials or with trials being planned — that have a neuroprotective focus or component.

One of the most intriguing and advanced initiatives in GA is Allergan’s study of the well-known glaucoma drug brimonidine (Alphagan) delivered in a long-acting, sustained-release format. In a 119-patient study begun in 2008 and led by Dr. Kuppermann, the drug, an alpha-2 adrenergic receptor agonist, was delivered via an intravitreal implant at higher concentration than its usual use as a topical glaucoma treatment. At 1 year, results were promising in terms of reducing lesion progression, but did not quite achieve statistical significance, and a second clinical trial was indicated to obtain stronger data.

This second study, called BEACON, has 311 patients and uses a higher-capacity implant. The study is ongoing, with each patient receiving 400 microns of brimonidine via intravitreal implant every 3 months for 21 months. The primary endpoint is change in the GA lesion area at 2 years. Secondary endpoints are change in BCVA and change in low-luminance BCVA.

Dr. Zacks has spent more than 15 years studying photoreceptor cell death and its impact on vision loss. His conclusion: Inhibiting the FAS-pathway through medical intervention is key to stopping unwanted photoreceptor cell death (apoptosis) in retinal detachment, wet and dry AMD, GA, and DR. Though blocking the FAS pathway is a specific therapeutic goal, it could well come under the broader category of neuroprotection.

The first human clinical trials of the neuroprotective ONL1204 peptide drug that Dr. Zacks’ spin-off company ONL Therapeutics will be conducting are in the planning stage. The 25,000 annual US cases of “macula-off” retinal detachment are the initial targets.

“The photoreceptor cell death that takes place between the time the retinal detachment occurs and the reattachment surgery is significant,” says Dr. Zacks. “That lost vision is not being regained. Our goal is to get our ONL1204 drug [an analogue of the small-molecule peptide Met12] injected into the patient’s eye as quickly as possible to shut off the FAS pathway and stop the cell death, which should allow much better visual outcomes in retinal detachment surgery.”

Dr. Zacks says ONL1204 should also be able to provide neuroprotection in GA, treating the root cause of vision loss in GA, which is photoreceptor cell death.

Finally, Genentech’s lampalizumab, currently in 2 large-scale phase 3 trials (CHROMA and SPECTRI) for GA, is a complement inhibitor with neuroprotective qualities. The large phase 3 studies should help to identify any neuroprotective qualities that lampalizumab possesses.

NEI Wants Ideas for Artificial Retinas

Big prize money offered in research challenge.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ The National Eye Institute (NEI) has begun the first stage of a federal prize competition designed to generate miniature, lab-grown human retinas. Over the next 3 years, pending availability of funds, NEI plans to offer more than $1 million in prize money to spur development of human retina organoids.

“None of the model systems currently available to researchers match the complex architecture and functionality of the human retina,” said NEI Director Paul A. Sieving, MD, PhD, in a press release. “We are looking for new ideas to create standardized, reproducible 3D retina organoids that can speed the discovery of treatments for diseases such as AMD and diabetic eye disease.”

The ideation stage of the 3D Retina Organoid Challenge aims to generate innovative ideas that can later be turned into concrete concepts. Running until August 1, 2017, the total prize purse for the ideation stage is $100,000.

“We’re looking for creative insights and application of new technology to unleash the full potential of retinal organoids. Our goal is for researchers to be able to generate or obtain retinal organoids easily so that they can be widely used for understanding diseases and testing drugs,” explained Jessica Mazerik, PhD, NEI challenge coordinator, in a press release. “To do this, we are encouraging entries from diverse teams of participants.”

The development stage of the challenge will require demonstration of a functional retina organoid prototype. This stage is planned to launch in fall 2017 and expected to offer $1 million in prize money. Full details of the 3D Retina Organoid Challenge prize competition are available at https://nei.nih.gov/3DROC .

Regeneron Partners in Big Genotyping Effort

Genetic evidence aids success in drug development.

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ Regeneron Pharmaceuticals, developer of the anti-VEGF therapy Eylea for a range of retinal diseases, has announced a major research initiative among the Regeneron Genetics Center (RGC), UK Biobank, and GSK to generate genetic sequence data from the 500,000 volunteer participants in the UK Biobank resource. The initiative will enable researchers to gain valuable insights to support advances in the development of new medicines for a wide range of serious and life-threatening diseases.

Regeneron says that genetic evidence has revolutionized scientific discovery and drug development in recent years by providing clear links between genes and disease. Currently, an estimated 90% of potential medicines entering clinical trials fail to demonstrate the necessary efficacy and safety, and never reach patients. Many of these failures are due to an incomplete understanding of the link between the biological target of a drug and human disease. By contrast, medicines developed with human genetic evidence have had substantially higher success rates and patient care has benefited.

UK Biobank has been collecting information and samples from its 500,000 participants for the past 10 years, and ensures that data provided to health researchers do not identify them. The RGC and GSK have committed an initial investment to enable the sequencing of the first 50,000 samples, to be completed before the end of 2017. Sequencing of UK Biobank’s samples will be performed at the RGC facility, one of the world’s largest human genetics sequencing centers. Sequencing of the full 500,000 samples in UK Biobank is expected to take 3 to 5 years.

Consistent with the founding principles of UK Biobank, these sequence data will be incorporated back into UK Biobank’s resource following a standard exclusivity period for GSK and Regeneron and made openly available to the broader scientific community. Research findings will also be submitted for publication in peer-reviewed journals.

“The costs of gene sequencing are falling, but doing it on a large scale involves highly specialized capabilities and is expensive — with an estimated cost of $150 million if all 500,000 participants are sequenced,” said Sir Rory Collins, UK Biobank principal investigator, in a press release. “That is why academia and industry working together is so important.”

The RGC previously sequenced DNA samples from more than 150,000 individuals and is now sequencing at a rate exceeding 150,000 individuals per year. The center has successfully applied large-scale human genetics to discover new drug targets and validate existing development programs, and it has collaborated with more than 35 institutions worldwide.