In a retrospective, noncomparative, consecutive case series, researchers sought to investigate the effects of systemic and local co-factors on the therapeutic response of intravitreal bevacizumab in diabetic macular edema, in order to assess how these co-factors could help in the management of DME, as well as help prognosticate the therapeutic response to anti-VEGF. While OCT has greatly improved our ability to diagnose and quantify the severity of DME, Alastair D. Bezzina, MD, ChM (Clin Ophth), FEBO, one of the study’s co-authors, says he believes that in addition to OCT, profiling DME and recognizing clues such as cystoid changes, subretinal fluid and the newly-coined DRIL (disorganization of the retinal inner layers) will help in gauging treatment success and planning therapy. He hopes to expand the current repertoire of biomarkers related to DME treatment.
The study included baseline imaging data and clinical records of 65 eyes (58 patients) with DME, secondary to type II diabetes mellitus. All eyes were anti-VEGF treatment-naïve as of January 2016. After three loading doses, central macular thickness, macular volume and BCVA were measured to explore correlations between risk factors and anatomical and functional outcomes.
“Macular volume mirrored the fluctuations seen in central macular thickness in many cases,” notes Dr. Bezzina. He says that one advantage of macular volume as an anatomical measure is that it considers the status of the parafoveal subfields, which play an important role in day-to-day activities such as reading, thanks to their influence on the psychophysical aspect of vision.
Participants in the study ranged between 46 and 84 years of age, with 41 males and 24 females. At baseline, mean CMT was 443.21 ±121.04 μm. Following the loading phase, mean CMT measured 390.86 ±125.92 μm, demonstrating a mean reduction of 52.35 μm (-11.23 percent, p<0.0005), which was highly significant and showed an overall positive therapeutic response. Highly significant changes were also observed in macular volume readings, with a mean reduction of -6.83 percent from baseline. An overall improvement in BCVA was also noted, with a mean reduction of 0.07, or a gain of three Snellen letters. No statistically significant correlations were noted between sex and secondary outcome measures such as glycemic control, raised cholesterol and lipoprotein levels, or baseline functional and anatomical parameters.
Females responded better to bevacizumab therapy, with a significantly greater reduction in CMT after the loading phase (-16.66 percent) than males (-8.04 percent), p<0.05. “As demonstrated in other studies, the possibility of sex-hormone-induced neurovascular protection may help in the resolution of [DME] when the effect of VEGF is mitigated with agents such as bevacizumab,” says Dr. Bezzina. “Not surprisingly, patients with PDR fared the worst anatomically, a finding which may be explained by increased VEGF levels in such patients.”
One interesting finding in the study was a reduced influence of systemic co-factors, including diabetic control, on therapeutic benefit. While the study doesn’t contraindicate the control of systemic factors as a means of limiting disease progression, Dr. Bezzina says it raises the question of whether tight blood pressure, glycemic and lipidemic control have any weight once the blood-retinal barrier is impaired and the vasogenic and inflammatory responses are triggered. He adds that larger, ideally prospective, studies are required to support this notion.
Patients with cystoid macular edema, a DME phenotype, demonstrated a poor result. Dr. Bezzina says this outcome may be explained by CME’s more pronounced inflammatory profile, which is less-responsive to anti-VEGF compared to a phenotype such as diffuse retinal thickening, which is thought to be more vasogenic. “Our hypothesis is that a vasogenic [DME] profile may demonstrate a better therapeutic response to anti-VEGF agents when compared to one which is predominantly inflammatory with more cystoid changes and the presence of subretinal fluid.” He says the latter may be more amenable to primary steroid treatment, but further studies are required to support this, especially considering the adverse effect profile of intraocular steroids and the fact that DRT and CME may, and generally do, co-exist. “Tackling both vasogenic and inflammatory aspects is the key to successful, long-term therapy of [DME] patients,” he says.
It’s important that clinicians keep in mind these systemic and ocular co-factors when managing DME patients so they can begin to think of alternative treatments if the response to anti-VEGF is poor, says Dr. Bezzina. He believes that DME may at times be either more inflammatory or more vasogenic. “This brings up the question of whether one class of agent may be more appropriate than another as a first-line treatment, depending on the [DME] profile,” he notes. “More comparative studies need to be performed in order to further affirm this notion.”
RGX-314 Back on Track
RGX-314, the subretinal gene therapy for neovascular AMD that has been progressing through FDA trials since 2017, is expected to begin a Phase IIb study during the first quarter of 2020, following a clinical hold order that the FDA had placed on the development of the therapy on October 18. The Phase IIb trial was rescheduled from the end of 2019 until early in 2020 after the developer of RGX-314, RegenxBio (Rockville, Maryland), filed a lawsuit against the FDA in federal court on November 7, challenging the agency’s clinical hold order.
Before the clinical hold order was issued, RegenxBio had submitted two investigational new drug applications for RGX-314: one for nAMD and one for diabetic retinopathy.
Tricia Truehart, vice-president, investor relations and communications at RegenxBio, says in a written statement that RGX-314 is being developed as a potential one-time subretinal treatment—not only for nAMD and DR, but for other chronic retinal conditions for which anti-vascular endothelial growth factor treatment is the standard of care. She says the treatment includes the “NAV AAV8 vector containing a gene encoding for a monoclonal antibody fragment. The expressed protein is designed to neutralize VEGF activity, modifying the pathway for formation of new leaky blood vessels and retinal fluid accumulation.”
In its complaint, the company said the FDA hadn’t offered “a reasoned explanation for issuing a clinical hold without advance warning.” In the interest of patient safety, the FDA had ordered the company to stop administering RGX-314 to existing and new study subjects (unless permitted by the agency) and to halt recruitment of study subjects, according to RegenxBio’s complaint. The lawsuit noted that the FDA said it was placing both INDs on hold because of unspecified “issues associated with their delivery systems” and that the FDA said it was “working on addressing” unspecified “device concerns.”
Though RegenxBio officials wouldn’t confirm if the FDA had lifted the clinical hold, they released this statement: “RegenxBio has received a letter from the FDA which provides us with information about their concerns around the third-party commercially-available devices that are used to deliver RGX-314 in our Phase I/IIa trial for the treatment of wet AMD. We will continue to work with FDA to address the concerns that they have raised regarding the devices, and support plans to initiate the RGX-314 Phase IIb study in subjects with wet AMD and file the IND for DR in Q1 2020.”
The FDA declined to comment for this article.
Forecasting IOP with A.I.?
Techniques that identify individuals in whom ocular hypertension is likely to progress to open-angle glaucoma may be able to assist clinicians with deciding on the frequency of monitoring and the potential benefit of early treatment. In a study from the University of Michigan, researchers tested whether Kalman filtering, a machine-learning technique, could accurately forecast intraocular pressure values five years into the future for individuals with OHT.1
The cohort study was a secondary analysis of data from individuals with OHT from the Ocular Hypertension Treatment Study. In it, individuals underwent tonometry and perimetry every six months for up to 15 years. Scientists trained, validated and tested a KF-OHT model to assess how well it could forecast IOP at up to five years, and compared the forecasts with results from the actual trial. They compared the KF for OHT with a previously developed KF for subjects with high-tension glaucoma (KF-HTG) and three traditional forecasting algorithms. Main outcomes were prediction error and root-mean-square error at 12, 24, 36, 48 and 60 months for mean deviation, pattern standard deviation and IOP.
Among 1,407 eligible participants (2,806 eyes), 809 (57.5 percent) were female and the mean (SD) age at baseline was 57.5 (9.6) years.
• For 2,124 eyes with sufficient measurements, KF-OHT was able to forecast MD values 60 months into the future within 0.5 dB of the actual value for 696 eyes (32.8 percent), 1 dB for 1,295 eyes (61 percent) and 2.5 dB for 1,980 eyes (93.2 percent).
• Among the five forecasting algorithms tested, KF-OHT achieved the lowest root-mean-square error (1.72 vs. 1.85 to 4.28) for MD values 60 months into the future.
• For eyes that progressed to open-angle glaucoma, KF-OHT and KF-HTG forecast MD values 60 months into the future within 1 dB of the actual value for 30 eyes (68.2 percent; CI, 54.4 to 82 percent) and achieved the lowest RMS error among all models.
Scientists wrote that the findings suggested that algorithms such as KF could forecast MD, pattern SD and IOP five years into the future for many individuals with OHT. They added that these algorithms may aid clinicians in managing OHT in patients. REVIEW
1. Garcia GP, Lavieri MS, Andrews C, et al. Accuracy of Kalman filtering in forecasting visual field and IOP trajectory in patients with ocular hypertension. JAMA Ophthalmol 2019; Nov 14. [Epub ahead of print].