For vitreoretinal specialists, the Retina Subspecialty Day at the American Academy of Ophthalmology’s annual meeting (AAO 2019) was jam-packed with new research, including first-time clinical trial results to updates on ongoing studies. Below, we’ve selected some of the posterior segment highlights from the meeting’s exciting scientific program.
In search of a better vitreous substitute
While there are various vitreous substitutes currently used in vitrectomy (i.e. air and expansile gases, perfluorocarbon liquids and silicone), each has limitations which can result in the need for postoperative posturing or further surgery for removal, as well as possible toxicity to ocular tissues. Rather, the ideal vitreous substitute would be biocompatible and degradable, while maintaining structural integrity and oxygenation to the retina.
Now, recent Phase 1 clinical trial results suggest a new – and potentially better – vitreous substitute might be on the way: Vitargus (American BriVision Corporation, CA, USA), an injectable, transparent hydrogel with a refractive index of 1.34. Its potential applications include retinal detachment repair, management of diabetic retinal hemorrhage with tractional retinal detachment, repair of penetrating eye trauma, including removal of intraocular foreign bodies.
Dr. Andrew Chang presented the results from the trial, which studied the safety and efficacy of intravitreal Vitargus. Eleven patients with retinal detachment or vitreous hemorrhage requiring vitrectomy were enrolled in the study. Vitargus was injected in its liquid form, with subsequent gelation. Follow-up occurred on days 1, 7, 14 postoperatively, then monthly up to day 120.
The trial found that Vitargus sets as a stable, semi-solid gel adhering to the retina and maintains its position without face-down positioning. Not only that, its optical properties allow patients to see well and it was shown to be a well-tolerated vitreous substitute. No apparent toxicity to the ocular tissues or systemic adverse events could be attributed to Vitargus.
Overall, the trial concludes that “the unique properties of Vitargus hold promise for its use following vitrectomy surgery”.
Is a longer-lasting therapy on its way?
While anti-VEGF is a mainstay of treating various conditions, the high number of injections is a frequent complaint. And in fact, the limited intraocular durability of current anti-VEGF agents is a potential contributor to the recurrence of disease.
Antibody Biopolymer Conjugates (ABCs) are a class of molecules engineered to maintain effective drug levels over longer periods of time than the current-generation anti-VEGFs. One in particular – KSI-301 – is an anti-VEGF ABC, with a possible dosing interval as infrequent as once every 12-20 weeks (following three loading doses) for patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME).
Dr. Charles C. Wykoff discussed results from current and ongoing studies of KSI-301 in patients with AMD, DME and retinal vein occlusion (RVO). Results from the Phase 1a single ascending dose study are in: KSI-301 was well-tolerated at all three dose levels (1.25, 2.5 or 5mg), and no drug-related adverse events, inflammation or dose-limiting toxicities were observed. After a single dose of KSI-301, investigators saw rapid visual and anatomic improvements as early as one-week post-treatment. This effect continued through week 4, with patients exhibiting a median BCVA improvement of +12.5 letters and a median CRT improvement of -120 microns from baseline. At week 12, following a single dose, median improvements were sustained with BCVA (+9 letters) and CRT (-121 microns).
Of course, there are additional trials ongoing to test its efficacy and safety. The Phase 1b open-label study of KSI-301 is evaluating two dosing levels, 2.5 and 5mg, in patients with nAMD, RVO and DME. In this study, patients receive 3 initial monthly injections with evaluation every 4 weeks through week 36. Meanwhile, a Phase 2 study with 400 treatment naïve patients with nAMD will receive either KSI-301 (5mg) every 12 to 20 weeks or aflibercept (2mg) every 8 weeks, after 3 monthly doses.
Do changes in retinal thickness impact visual outcomes in nAMD patients?
Dr. Usha Chakravarthy and investigators hypothesized that patients who experienced greater variations in retinal thickness when treated with anti-VEGF for nAMD would have worse visual outcomes than patients with less variation. They conducted a meta-analysis of the IVAN and CATT trials, extracting foveal center point thickness (CPT) measurements for a total of 1,711 patients.
Patients were grouped by quartiles based on S-CPT (standardized CPT) standard deviation (SD). In patients with the least S-CPT variation, mean BCVA at the final visit was 73.2 letters (SD, 14.2); while for those with the most S-CPT variation, the final mean BCVA was 59.4 letters (SD, 14.2).
These results led the investigators to conclude that “fluctuation in retinal thickness, despite optimal treatment frequency, is adversely associated with visual outcome”.
Uveitis Clinical Trial Update
Four clinical trials – MUST, POINT, MERIT and ADVISE – test various therapies to treat uveitis. According to a synopsis provided by Dr. Douglas Jabs, “approximately 40% of eyes with uveitic macular edema will have persistent or relapsed edema at 2 years of treatment, despite control of evident inflammation and use of adjunctive regional corticosteroid injections”.
The MUST trial compared systemic therapy with oral corticosteroids and immunosuppression versus regional (ocular) therapy with the 0.59mg fluocinolone acetonide intraocular implant (Retisert) for noninfectious intermediate, posterior, or pan-uveitides. The investigators found the risk of blindness was nearly doubled in the regional therapy group due to retinal damage from relapse, and this group also saw significantly increased rates of ocular side effects like cataract, elevated IOP and glaucoma. This led the authors to conclude that “systemic therapy may be a better initial choice”.
The POINT Trial compared periocular triamcinolone, intraocular triamcinolone and intraocular dexamethasone implant (Ozurdex) for treating uveitic macular edema. Both intravitreal triamcinolone and intravitreal dexamethasone were superior to periocular triamcinolone; and dexamethasone was noninferior to intravitreal triamcinolone. This led the authors to conclude that intravitreal approaches might be preferred when treating uveitic macular edema.
The MERIT trial is currently ongoing and is looking at the comparative effectiveness of intravitreal dexamethasone implant versus intravitreal ranibizumab versus intravitreal methotrexate injections for the treatment of persistent or relapsed uveitic macular edema.
Another ongoing trial is ADVISE, a randomized comparative effectiveness trial of adalimumab versus conventional immunosuppression with antimetabolites of calcineurin for patients with noninfectious intermediate, posterior or panuveitis.
All in all, it’s an exciting time to work in vitreoretina – with new molecules, therapies and innovation all showing promise for improved visual outcomes for patients suffering from sight threatening back-of-the-eye conditions.
Editor’s Note: The American Academy of Ophthalmology’s annual meeting (AAO 2019) was held from October 12 to 15, 2019, in San Francisco, California, USA. Reporting for this story also took place at AAO 2019.
