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A New Era in Retinal Disease Management: Targeting New Pathways and Investigating Novel MOAs

  • Authors: Caroline Baumal, MD
  • CME / ABIM MOC Released: 5/26/2022
  • Valid for credit through: 5/26/2023
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.50 ABIM MOC points

    Optometry - This course is COPE approved for 0.5 hours of CE credit.

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    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for ophthalmologists, diabetologists, endocrinologists, and optometrists.

The goal of this activity is for learners to have a better understanding of new and emerging treatments for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) so they can optimize outcomes for patients with retinal disease as more treatments with novel mechanisms of action (MOAs) or dosing become available.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • VEGF pathway 
    • Angiopoietin (Ang) pathway in disease pathogenesis 
    • MOAs of new treatments for nAMD and DME  


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  • Caroline Baumal, MD

    Professor of Ophthalmology and Vitreoretinal Surgery
    New England Eye Center
    Tufts Medical Center
    Boston, Massachusetts


    Disclosure: Caroline Baumal, MD, has the following relevant financial relationships:
    Consultant or advisor for: Apellis; Genetech; Novartis
    Speaker or member of speakers bureau for: Regeneron


  • Pakinam Aboulsoud, PharmD

    Medical Education Director, Medscape, LLC


    Disclosure: Pakinam Aboulsoud, PharmD, has no relevant financial relationships.

  • Christin Melton, ELS

    Associate Medical Education Director, Medscape, LLC


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  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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    COPE Credit

    Postgraduate Institute for Medicine is accredited by COPE to provide continuing education to optometrists.
    Credit Statement: This course is COPE approved for 0.5 hours of CE credit. Activity #123431 and Course ID 77008-TD. Check with your local state licensing board to see if this counts toward your CE requirement for re-licensure.

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A New Era in Retinal Disease Management: Targeting New Pathways and Investigating Novel MOAs

Authors: Caroline Baumal, MDFaculty and Disclosures

CME / ABIM MOC Released: 5/26/2022

Valid for credit through: 5/26/2023


Activity Transcript

Caroline Baumal, MD: Hello. I'm Dr Caroline Baumal, professor of ophthalmology and vitreoretinal surgery at the New England Eye Center, Tufts Medical Center, in Boston. Welcome to this program titled, "A New Era in Retinal Disease Management: Targeting New Pathways and Investigating Novel MOAs." Today, I will be discussing novel pathways and newer mechanisms of action that may permit more durable treatment for patients with neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME).

The current mainstream of therapy for these disorders is monotherapy with intravitreal anti-vascular endothelial growth factor (VEGF) injections. This treatment has revolutionized our therapy of neovascular AMD, DME, and diabetic retinopathy over the last 2 decades. Intravitreal anti-VEGF agents have slowed disease progression and led to moderate visual acuity gains. In some parts of the world, these treatments have even reduced legal blindness by up to 50%.

If we look at how we treated these disorders historically prior to 2000, we had laser photocoagulation as the primary treatment for DME and diabetic retinopathy. For neovascular AMD, we had laser treatment and photodynamic therapy. Since the advent of intravitreal anti-VEGF injections, we found that we don't have to be satisfied with just preventing vision loss, and that we can actually improve visual acuity. There are some commercially approved intravitreal anti-VEGF agents, and there are other treatments, including corticosteroids. Most recently, there have been 2 approvals: faricimab and a port delivery system with ranibizumab.

Although we have anti-VEGF monotherapies, there is room for improvement in how we treat our patients. These agents typically have a short duration of effect. Because of that, we need to do frequent intravitreal injections. This can place a treatment burden not only on patients, but also on their families and caregivers. The other issue with intravitreal injections is that there may not be a clear endpoint as to when treatment can stop, and this can cause stress for the patient.

Despite the success of intravitreal anti-VEGF monotherapy, 30% of patients continue to lose vision. Also, long-term efficacy can be disappointing, so patients may become lost to follow-up. There are also unmet needs, such as fibrosis and geographic atrophy. Real-world outcomes have shown that the visual acuity gains and that the number of intravitreal injections do not match those from clinical trials -- we have this discrepancy between how patients do in the real world and how they do in clinical studies.

So, current anti-VEGF agent have some limitations related to the frequency of treatment, the frequency of patient visits, limitations in efficacy, and side effects. What are the solutions for this? Well, to solve a high frequency of treatments or the number of visits, the solution is to find an agent with a longer duration of effect or a new mechanism of action. With regards to limitations in efficacy, the solution could be either earlier intervention or finding an agent with a new mechanism of action. With regards to side effects, the solution might also be to add new modes of delivery.

Some of the new approaches to current anti-VEGF agent limitations include discovering new anti-VEGF agents, looking at combination therapy (for example, combining an anti-VEGF agent with another agent that has a different mechanism of action), looking at new drug structures, considering systemic therapy or topical therapy, or using a sustained or novel drug delivery device.

There are multiple emerging therapeutic agents and treatment delivery systems being evaluated to improve durability and efficacy for patients with neovascular AMD or DME. I'll be reviewing some of those today, including faricimab, brolucizumab, abicipar, KSI-301, OPT-302, and gene therapy.

Let's start with the VEGF and the angiopoietin (Ang)–Tie signaling pathway. The angiopoietin tyrosine protein kinase system is a protein receptor system that plays a complementary role in regulating vasculature alongside VEGF. Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are 2 distinct vascular growth factors that bind to the Tie-2 transmembrane receptor.

Each molecule leads to different reactions when bound. The Ang/Tie2 signaling pathway is essential for normal vascular development and homeostasis. Ang1 is a full agonist on the Tie2 receptor. This results in phosphorylation of the receptor, thus inhibiting vascular permeability and preserving vascular stability. By contrast, Ang2 acts as either a partial agonist or an antagonist of Ang1, which inhibits phosphorylation of the Tie2 transmembrane receptor, thereby deactivating the entire pathway and disrupting vascular stability, which leads to leakage and neovascularization. Although Ang1 and Ang2 bind to the same receptor, each agent produces opposing vascular effects. I like to consider Ang1 as the good player.

When Ang1 is bound to Tie2, we have vascular stability. Ang2, however, is the bad player and leads to vascular instability, neovascularization, and leakage. In pathological conditions such as hyperglycemia, hypoxia, or oxidative stress, Ang2 is markedly upregulated and competes with Ang1 for the Tie2 receptor, thus inhibiting Ang1-induced Tie2 activation and vascular stability.

VEGF is another key regulator in the process of retinal angiogenesis. VEGF is a vascular permeability factor or signaling protein in the platelet-derived growth factor family and has 4 subtypes: VEGF-A, VEGF-B, VEGF-C, and VEGF-D. These are received by 3 transmembrane tyrosine kinase receptors: VEGFR-1, VEGFR-2, and VEGFR-3. Each VEGF subtype can lead to a slightly different biological pathway. The primary clinical research has focused on VEGF-A and B, the subtypes most implicated in the growth and maintenance of new vasculature.

Binding of VEGF-A to the VEGFR-2 receptor is directly involved in angiogenesis. VEGF-A is the primary target in the treatment of neovascular AMD. In conjunction with the upregulation of VEGF in similar disease states, coexpression of these 2 permeability factors -- Ang2 and VEGF -- has been reported to accelerate neovascularization in the developing retina and ischemic retina models. Ang1 was found to be decreased in capillary vasoregression, vascular permeability, and retinal hypoxia, supporting inhibition of Ang2 function by its balancing factor.

Faricimab is the first bispecific antibody designed for intraocular use. Bispecific means it's a single molecule with 2 targets. There is anti-Ang2 fragment antigen binding (Fab), which is designed to bind and neutralize Ang2. There's also anti-VEGF-A Fab, which is designed to bind and neutralize VEGF-A. There is also a modified fragment crystallizable (Fc) receptor to reduce systemic exposure and inflammatory potential.

Faricimab was recently approved by the FDA for treatment of neovascular AMD and DME. Faricimab was approved for treatment of DME based on 2 phase 3 pivotal trials: YOSEMITE and RHINE. In these studies, faricimab was compared with aflibercept given as per label. There were 2 faricimab arms. One was faricimab given every 8 weeks, and the other was faricimab given according to a personalized treatment interval (PTI). This was a protocol-driven treat-and-extend regimen, where after 4 initial loading doses (1 every 4 weeks), patients could have the interval extended up to every 16 weeks or reduced to every 4 weeks based on optical coherence tomography (OCT) and visual acuity criteria.

The primary endpoint of the study and year 2 results showed that vision gains with faricimab in the every-8-week arm and in the PTI arm with dosing up to every 16 weeks were noninferior to aflibercept given every 8 weeks at year 1. This was maintained through year 2. In evaluating patients in the PTI arm, 78% of patients in the YOSEMITE and RHINE studies were at an interval of every 12 weeks or every 16 weeks at week 96. At week 96, just over 60% of patients were in the every-16-week interval.

One of the notable secondary endpoints in the YOSEMITE and RHINE trials of faricimab for DME was greater reductions in central subfield thickness (CST) in both faricimab arms (ie, the arm with faricimab given every 8 weeks and the PTI arm of faricimab given up to every 16 weeks) when compared with aflibercept given every 8 weeks. Also, the proportion of patients with 2 or more steps of improvement in the Diabetic Retinopathy Severity Score was consistent across all studies and all treatment arms.

Faricimab was approved for the treatment of neovascular AMD based on the TENAYA and LUCERNE trials, which are 2 paired phase 3 pivotal trials. In these studies, faricimab was injected at 1 of 3 fixed treatment intervals after 4 initial loading doses: every 8 weeks, every 12 weeks, or every 16 weeks. The treatment interval was based on disease activity assessments at weeks 20 and 24. Faricimab was compared with aflibercept given every 8 weeks after 3 loading doses, as per the label.

In the TENAYA and LUCERNE trials, faricimab demonstrated durable vision gains at week 48. Approximately 45% of patients were being treated at an interval of every 16 weeks, and almost 80% of patients were being treated at an interval of every 12 or every 16 weeks at the primary endpoint.

Faricimab resulted in meaningful CST reductions that were comparable to aflibercept given every 8 weeks. This was achieved with almost 80% of faricimab patients being dosed every 12 or more weeks. Looking at safety, there were low rates of adverse events of intraocular inflammation in the trials, and there were no cases of retinal vasculitis in either study.

To summarize, in patients with DME or neovascular AMD, faricimab demonstrated noninferior vision gains and improved anatomic outcomes even at extended dosing intervals. For DME, the primary endpoint was met. Best corrected visual acuity gains with faricimab given every 8 weeks or using a PTI with up to every 16-week dosing were noninferior to aflibercept given every 8 weeks at 1 year, and this was maintained throughout 2 years of the study.

There were improved anatomic outcomes with faricimab vs aflibercept. This included improved changes in CST favoring faricimab. Also, more faricimab-treated eyes achieved absence of DME and absence of intraretinal fluid. As well, strong durability was seen, with up to 65% of patients on every 16-week dosing and 78% of patients on every 12- or 16-week dosing at the end of year 2.

With regard to neovascular AMD, best-corrected visual acuity gains with faricimab given up to every 16 weeks were noninferior to aflibercept given every 8 weeks at week 48. There were meaningful reductions in CST with faricimab compared with aflibercept. Durability was also shown at week 48 with faricimab, with 80% of eyes on every 12- or 16-week dosing and 45% of eyes on every 16-week dosing. Looking across all these studies, faricimab was well tolerated and there was no case of occlusive retinal vasculitis noted. There are long-term extension studies currently being done in each disease state.

KSI-301 is a novel anti-VEGF agent. It is on this antibody biopolymer conjugate (ABC) platform designed for a larger molecular weight potentially to allow longer treatment duration. Whereas ranibizumab weighs 48 kDa and aflibercept weighs 115 kDa, KSI-301 is a much heavier 950 kDa. The integrated properties of the ABC platform offer the potential of a longer-acting intravitreal therapeutic with a long intraocular half-life, excellent retinal bioavailability, deeper inhibitory potency, and fast systemic clearance.

KSI-301 is in pivotal programs for wet neovascular AMD, DME, retinal vein occlusion, and nonproliferative diabetic retinopathy. Most recently, data were reported from the DAZZLE program for KSI-301 in neovascular AMD. KSI-301 did not meet the primary endpoint when compared with aflibercept given every 2 months. We'll be hearing more about other phase 3 trials of KSI-301 in the near future.

OPT-302 is a novel molecule that inhibits VEGF-C and VEGF-D. Ranibizumab, brolucizumab, and bevacizumab inhibit VEGF-A; and aflibercept inhibits VEGF-A, VEGF-B, and placental growth factor. OPT-302 is unique in that it inhibits VEGF-C and VEGF-D, which become elevated when VEGF-A is inhibited. Combining OPT-302 with one of the other anti-VEGF agents leads to broader VEGF inhibition.

OPT-302 is being evaluated in combination with another anti-VEGF agent to treat neovascular AMD with the potential to offer superior visual acuity gains. In the phase 2B study, OPT-302 combined with ranibizumab demonstrated a 3.4-letter improvement in vision gains compared with ranibizumab alone. There are currently 2 ongoing phase 3 trials evaluating OPT-302 in neovascular AMD. It's also being studied for DME.

Brolucizumab is an FDA-approved agent for neovascular AMD. Its unique property is that its molecular weight of 26 kDa is much less than the molecular weight of the other agents. It is a single-chain antibody fragment. Because of its low molecular weight, a high molar dose can be achieved. It was approved for neovascular AMD based on findings from the phase 3 HAWK and HARRIER trials, which compared brolucizumab given every 8 or every 12 weeks with aflibercept given every 8 weeks in neovascular AMD. The primary endpoint was met, showing that brolucizumab was noninferior to aflibercept. Brolucizumab also appeared to dry better on OCT.

Brolucizumab was also studied for DME in the phase 3 KITE and KESTREL studies. Brolucizumab met the primary endpoint of noninferiority to aflibercept in best-corrected visual acuity at 1 year. It also showed better drying on OCT. Although the durability of brolucizumab is promising, there were post-approval safety concerns. Shortly after approval, there were reports of intraocular inflammation, which could be associated with retinal vasculitis and retinal occlusive events.

Overall, when data from the HAWK and HARRIER trials were looked at post-approval, it was noted that about 4.6% of eyes had intraocular inflammation, 3.3% had intraocular inflammation with vasculitis, and 2.1% had intraocular inflammation with retinal vasculitis and retinal occlusion. The risk of developing intraocular inflammation of any form and losing 15 or more letters was 0.7%. The cause of this remains incompletely understood.

Abicipar is another novel molecule. This is a DARPin (designed ankyrin repeat protein) molecule that was designed to offer greater durability. Again, it's a small molecule measuring about 34 kDa. This molecule blocks all forms of VEGF-A. Abicipar was evaluated for neovascular AMD in the phase 3 CEDAR and SEQUOIA studies. Abicipar is also challenged by intraocular inflammation, which was observed in about 15% of abicipar-treated eyes. Because of this, the FDA did not approve abicipar.

I think abicipar and brolucizumab highlight some of the challenges in finding novel treatments that have extended durability. Safety is very important, so as we evaluate new agents, we have to be concerned about potential adverse events and make sure they are limited in our patients who need treatment.

The last topic to touch on is gene therapy. The eye is ideal for this because it is small. The retina is easily accessible, so we can have precise drug delivery. The retina can also be directly examined to monitor the effects of therapy. There may also be some immune privilege in the retina and the blood retinal barrier.

There has been some success with gene therapy. The FDA approved voretigene neparvovec in December 2017. It was the first gene therapy approved to treat an inherited retinal disease and the first gene therapy in ophthalmology. This adeno-associated virus (AAV) vector-based gene therapy is approved to treat patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

With subretinal gene therapy for neovascular AMD, a 1-time treatment could potentially offer sustained efficacy. For gene therapies currently being evaluated, the candidate protein is inserted into the gene -- for example, a protein that directs production of an anti-VEGF agent. This may be administered into the subretinal space. After transduction, protein synthesis occurs, with sustained protein expression over several years.

RGX-314 uses a novel AAV8 vector to deliver an anti-VEGF Fab that induces production of an anti-VEGF similar to ranibizumab. RGX-314 can be delivered once by a subretinal injection or a suprachoroidal injection. ADVM-022 is another potential gene therapy being evaluated for treatment of neovascular AMD. It is an intravitreal injection that induces transduction of a protein that is similar to aflibercept. GT005 is investigational single dose. One-time gene therapy is designed to induce expression of complement factor I. This therapy is designed to help restore the balance between the complement system following a single subretinal injection.

To summarize, these are exciting times in retinal therapy. There are many investigational therapeutics that leverage unique mechanism of actions and demonstrate potential to address unmet needs in patients with neovascular AMD and DME. These unmet needs include improving durability to reduce the treatment burden and increasing the efficacy of treatment to break the current ceiling in visual acuity. Of course, safety is so important. We need to make sure that any new or novel treatments we have are safe for our patients. Lastly, we know that patients have heterogeneous disorders and different expression of disease. Future treatments may help us predict individualized patient responses and develop individualized therapy.

Thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.

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