Bispecifics treatment landscape ‘bustling’ in wet AMD, DME
Key takeaways:
- Bispecifics are a relatively new area in ophthalmology.
- In 2022, faricimab was the first-ever FDA-approved bispecific agent for wet AMD and DME.
Bispecific agents appear promising in broadening the treatment landscape in wet age-related macular degeneration and diabetic macular edema, but much remains to be learned about this emerging class of agents.
“Bispecifics essentially incorporate another mechanism of action into the treatment strategy, which could lead to improved efficacy or durability without necessitating a separate injection,” Christina Y. Weng, MD, MBA, professor in the department of ophthalmology and fellowship program director of vitreoretinal diseases and surgery at Baylor College of Medicine, told Healio. “Theoretically, targeting more pathogenic elements may also mean better overall control of disease.”
It is important to remember that the pathways involved in these diseases are closely intertwined.
“Inhibiting one or two parts in isolation could have a ripple effect upstream or downstream,” Weng said. “Since bispecifics are still a relatively new area in ophthalmology, safety must be monitored carefully, both in the clinical trial setting as well as in the clinical practice setting.”
‘Fantastic’ advancement
In January 2022, the FDA approved Vabysmo (faricimab-svoa, Genentech) as the first-ever bispecific antibody that targets both angiopoietin-2 and VEGF-A for the treatment of wet AMD and DME.
“The approval was based on the excellent safety and efficacy demonstrated in the pivotal phase 3 TENAYA/LUCERNE and YOSEMITE/RHINE trials,” Weng said.
In the TENAYA and LUCERNE trials, 1,329 patients with treatment-naive AMD were assigned 1:1 to receive 6 mg faricimab (TENAYA, n = 334; LUCERNE, n = 331) up to every 16 weeks or 2 mg aflibercept (TENAYA, n = 337; LUCERNE, n = 327) every 8 weeks.
Best corrected visual acuity with faricimab was noninferior to aflibercept in patients in the TENAYA trial (adjusted mean change, 5.8 letters; and 5.1 letters) and the LUCERNE trial (adjusted mean change, 6.6 letters; and 6.6 letters). Moreover, results showed comparable rates of ocular adverse events between patients who received faricimab in the TENAYA trial (36.3% vs. 38.1%) and the LUCERNE trial (40.2% vs. 36.2%).
In the YOSEMITE/RHINE trials, 1,891 patients with vision loss due to center-involving DME were assigned 1:1:1 to 6 mg faricimab every 8 weeks (YOSEMITE, n = 315; RHINE, n= 317), 6 mg faricimab per personalized treatment interval (YOSEMITE, n = 313; RHINE, n= 319) or 2 mg aflibercept (YOSEMITE, n = 312; RHINE, n= 315) every 8 weeks up to 100 weeks.
There were robust vision gains and anatomical improvements in patients who received faricimab in both trials, demonstrating the potential for faricimab to extend the durability of treatment among patients with DME.
“Initial real-world studies have corroborated the efficacy observed in the registration studies, and it is fantastic that we now have an additional therapeutic option to offer our patients affected by wet AMD or DME,” Weng said. “One important point is that it is impossible to separate out the effects of a bispecific agent, which can make cross-trial and product comparisons challenging. With faricimab, the proportion of efficacy that is attributed to the anti-VEGF vs. the anti-Ang-2 component cannot be delineated.”
Agents in the pipeline
Other bispecific agents are currently in the pipeline for wet AMD and DME.
“One of my favorite parts of retina is how bustling the investigational landscape is. There are several bispecific molecules that are actively being evaluated,” Weng said.
RO-101 (RevOpsis Therapeutics) is a fully humanized VEGF-A/Ang-2 inhibitor that uses a novel antigen-binding platform. The agent is being examined for wet AMD, DME and retinal vein occlusion, according to Weng.
“While development of RO-101 is still in the preclinical phase, in vitro experiments have demonstrated excellent anti-angiogenic activity with binding affinities that exceed those of currently available agents,” she said. “Another anti-VEGF/anti-Ang-2 bispecific molecule under evaluation for wet AMD and diabetic macular edema is AM712 (AffaMed Therapeutics), and the phase 1 trial for patients with wet AMD is ongoing. In addition, AM305/AG-73305 (AffaMed Therapeutics/Allgenesis Biotherapeutics) is a multispecific fusion protein that blocks VEGF as well as several integrins that recently completed enrollment for a phase 2 study in patients with DME and is also being evaluated for wet AMD.”
Bispecific antibody agents under development by Innovent Biologics include IBI324, a recombinant anti-VEGF-A/anti-Ang-2 antibody in phase 1 for DME; IBI333, a fusion protein that inhibits VEGF-A and VEGF-C in phase 1 for wet AMD; and IBI302, a multispecific antibody that blocks VEGF, C3b, and C4b in phase 2 for wet AMD, according to Weng.
“UBB2048 (UNITY Biotechnology) has a bispecific antibody in preclinical stages that targets the Tie2/VEGF pathway in retinal vascular diseases,” she said. “Lastly, KSI-501 (Kodiak Sciences) is an anti-VEGF/IL-6 bispecific antibody that utilizes an antibody biopolymer conjugate platform that is under development in preclinical stages for the treatment of retinal vascular diseases.”
Ongoing research
While treatment approaches that primarily target VEGF-A have shown good efficacy, it is reasonable to hypothesize that concurrently targeting other pathogenic factors may lead to even better efficacy or greater durability, Weng said.
“The research being done on bispecific and multispecific molecules interests me because wet AMD and DME are complex diseases that involve multiple intertwining pathways,” she said. “For example, VEGF-A blockade can upregulate VEGF-C levels and may partly explain the incomplete response to anti-VEGF injections in some patients. Therefore, the concept of molecules such as IBI333 that inhibit both VEGF-A and VEGF-C is appealing. I look forward to what the phase 1 dose escalation study for IBI333 will find.”
Also intriguing are the bispecific agents that target both angiogenesis and complement pathway-mediated inflammation, Weng said.
“These could benefit not only patients with wet AMD who can ultimately lose vision from macular atrophy despite angiogenic control but also patients with geographic atrophy undergoing treatment with complement inhibitors, which can increase the risk for developing exudation,” she said. “We also do not yet know whether bispecifics show promise in combination with other therapies in wet AMD and DME. I am especially curious about how bispecifics could work in combination with intravitreal steroids for DME, which is a multifactorial disease wheremany patients currently have an incomplete response when treated with anti-VEGF-A monotherapy.”
Looking ahead, “I expect that we will learn from real-world experiences with faricimab whether combining treatment with a steroid will improve outcomes,” Weng said.
Editor's note: This article was updated on July 18, 2023, to clarify the dosage data in the TENAYA/LUCERNE and YOSEMITE/RHINE trials.
References:
- Heier JS, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)00010-1.
- Khanani AM, et al. Eye (Lond). 2023;doi:10.1038/s41433-023-02553-5.
- Kim E, et al. Discontinuation, switching, and other long-term routine clinical practice treatment patterns among patients with diabetic macular edema initiating anti-VEGF: 6-year follow-up using the IRIS Registry. Presented at: Association for Research in Vision and Ophthalmology meeting; May 1-4, 2022; Denver.
- Wykoff CC, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)00018-6.
For more information:
Christina Y. Weng, MD, MBA, of Baylor College of Medicine, can be reached at christina.weng@bcm.edu.
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