Since the introduction of bevacizumab (Avastin, Genentech) as an off-label treatment in 2005, and the FDA approval of ranibizumab (Lucentis, Genentech) in 2006, intravitreal injection (IVI) of antibodies to vascular endothelial growth factor (anti-VEGF) have been the mainstay of treatment for a multitude of ocular conditions including neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), retinal vein occlusion (RVO), and diabetic macular edema (DME). The treatment burden on patients has been relatively high, consisting of injections as frequently as every 28 days.

With the introduction of pharmaceutical variations, the treatment burden has been decreased in some patients, with aflibercept (Eylea, Regeneron) as long as 8 weeks and brolucizumab (Beovu, Novartis) as long as 12 weeks between injections with continued efficacy. However, many patients with less responsive disease variants need to come in consistently every 4 weeks to maintain their current vision. This places a strain on both the healthcare system and on each individual patient, many of whom drop out of treatment and consequently suffer permanent vision loss.

Novel treatments aim to decrease this high level of treatment burden on patients, with some potentially extending time between injections as far as 6 months. A variety of modalities are being employed in this attempt, including constructing a more effective anti-VEGF molecule, inserting a mechanism for sustained medication delivery, and targeting a new mechanism of action in the inflammatory disease cascade.

The number of needles in a patient’s eye is reduced while maintaining treatment efficacy and visual outcome. This impacts practice scheduling as decreased treatment frequency would allow the practice to see a greater number of total patients. For physicians and technicians, days could be less hectic with fewer scheduled daily injections. Still, staff would need to adjust to some of the nuances of these new treatment possibilities.

Scheduling

A current “injection only” visit for a patient can be completed in as little as 30 minutes and facilitates as many as 40-50 appointments per day for each physician in the practice.

At least one novel treatment, Roche’s faricimab, would maintain this methodology. A bispecific antibody against VEGF and angiopoietin-2 (Ang2), faricimab would be drawn up and injected similarly to anti-VEGF medications currently utilized; however, faricimab has the added benefit of halting the disease process via two separate mechanisms of actions. Phase 2 AVENUE and STAIRWAY trials demonstrated noninferiority to current treatment protocols. Early results of Phase 3 TENAYA and LUCERNE as well as YOSEMITE and RHINE studies results suggest >70% of patients being able to extend time between injections to 12 weeks and >50% to 16 weeks after initial loading doses.

In addition to this novel medication, the Phase 3 PULSAR and PHOTON studies are investigating an increased dose of aflibercept (8 mg compared to 2 mg) at 12-16 week intervals, which would be administered without any changes to the current methodology.

Preparation

Some of these novel treatments would require more effort and time on behalf of the technicians preparing them.

The first of these, Opthea’s OPT-302, is a VEGF C/D trap molecule designed to be used in conjunction with current anti-VEGF-A treatments. As it comes frozen, it requires 40 minutes to defrost in the refrigerator prior to injection and would require each facility to have a freezer and maintain an appropriate cold chain. Additionally, it is given in conjunction with standard of care anti-VEGF, so the patient receives two injections with a 15-minute period between to ensure IOP stabilization, which lengthens the visit. Phase 3 ShORe and COAST studies are currently analyzing OPT-302’s efficacy treating nAMD in combination with ranibizumab and (aflibercept, Regeneron), respectively.

Kodiak Science’s KSI-301 is an antibody biopolymer conjugate, a novel method of attaching the anti-VEGF molecule to a polymer that would last longer in the eye, thus increasing both bioavailability and durability. Early results also suggest a decreased systemic absorption of anti-VEGF and a decreased half life in the body, thus decreasing any potential adverse effects. However, this polymer causes the medication to be extremely viscous, which roughly doubles the amount of time required to both draw up and actively inject. There are a variety of active Phase 2/3 studies including DAZZLE for nAMD, GLEAM/GLIMMER for DME, BEACON for RVO, and GLOW for diabetic retinopathy analyzing its efficacy in each of the different diseases entities treated.

Education

Two of the proposed novel treatments are enacted via gene therapy in a viral vector, which would require increased patient education.

Adverum’s ADVM-022, an adeno-associated virus, contains complimentary DNA to generate an aflibercept medicine and can be administered in a standard intravitreal injection.

Regenxbio’s RGX-314 is an adeno-associated virus coding for a ranibizumab-like medicine, which requires vitrectomy and intraoperative injection via cannula into a subretinal bleb.

Techs will need to educate patients on the surgical intervention for treatment (which also requires OR scheduling) along with the need for close immediate follow-up and an initial increase in their treatment burden.

Alternative technology

Another surgical alternative being proposed is Genentech’s port delivery system, or PDS, which is an apparatus installed in the OR with a reservoir of anti-VEGF medication. Current studies utilize ranibizumab, with recruited patients having shown a positive response to IVI but with need for frequent injections. This novel system releases medication slowly into the vitreous over a period of months. The Phase 2 LADDER study’s high-dose arms suggest a refill as infrequently as every 15 months, and 98% of the study participants are able to go 6 months without an injection. Phase 3 ARCHWAY and PORTAL are currently underway to analyze its efficacy.

Although it is necessary to undergo implantation in a surgical suite using vitrectomy equipment, the refill would be performed in a clinic setting, providing overall decreased treatment burden moving forward for the patient.

Advancing treatment

With the prevalence of nAMD alone at roughly 1% in the United States, roughly 3 million patients rely on regular injections for sustained vision. Combined with DR, RVO, and DME, this number rises dramatically. This burden on both the patient and healthcare system stands to be greatly reduced with an improvement in therapy that results in an increase in time between each required treatment.

More treatment options with varying procedures in storing, preparing, and applying may translate to decreased efficiency relative to the current homogenous process for anti-VEGF treatment. Standardization across these new processes will be a challenge but is needed for maintaining safety. The variability and treatment options may require more time to select optimized treatment, as well as chair time with the patient regarding individualized risks and benefits of each treatment.

With proper scheduling, technician training, and patient education, these described novel treatments are our most promising upcoming possibilities to take the next step in advancing treatment. OP

Luke Mein, MD is a graduate of the Long School of Medicine in San Antonio, TX.

Huy Nguyen, MD, is an ophthalmology resident physician at the University of Texas Health Science Center in San Antonio, TX.

Michael Singer, MD, is clinical professor of ophthalmology at the University of Texas Health Science Center in San Antonio, TX. He is also the director of clinical research at Medical Center Ophthalmology in South Texas. In 2018, he was inducted into the Retina Hall of Fame. Disclosures: Dr. Singer reported relationships with Aerie, Allegro, Allergan, DRCR, Eyepoint, Genentech, Icon, Ionis, Kalvista, Kodiak, Mallinckrodt, Novartis, Opthea, Optos, Regeneron, Santen, Senju, Spark, and Sydnexis.