Specialists weigh strengths, limitations of AMD and DME strategies currently at hand
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Novel pharmacotherapies for retinal vascular diseases are pursuing the dual goal of increased efficacy and longer duration of action.
The journey is not an easy one, but meaningful progress has been made despite the hurdles, disruptions and detours found along the way. With faricimab and high-dose aflibercept already on the market and the Port Delivery System undergoing further optimization, sufficient data from trials and real-world experience have been generated to realistically support the hope that more robust disease control and less frequent administration are possible.
“These options are likely the first of many steps toward these two goals,” Healio | OSN Retina/ Vitreous Section Editor Andrew A. Moshfeghi, MD, MBA, said.
Research is striving for further improvement, but patients are already experiencing a change for the better.
“If we ask patients whether these new offerings represent a meaningful change in their therapy compared to what we had before, I think the answer to that question is yes. Many of them have seen their treatment interval prolonged by at least a couple of weeks, some by a whole month, and for patients who were not favorably responding or optimally responding to the existing therapies, there is often a noticeable improvement from the switch. The other goal of increased potency is also starting to be realized with more robust control of neovascular AMD and DME,” he said.
Faricimab
In January 2022, the FDA approved Vabysmo (faricimab, Genentech) following the positive results of the phase 3 TENAYA and LUCERNE trials in wet age-related macular degeneration and YOSEMITE and RHINE trials in diabetic macular edema. Two-year outcomes, published a few months later, showed that more than 60% of participants who received faricimab could be treated every 4 months and nearly 80% every 3 months, achieving vision gains comparable to aflibercept every 2 months. For all trials, safety was comparable between the aflibercept and faricimab arms.
Healio | OSN Retina/Vitreous Board Member Arshad M. Khanani, MD, MA, was involved in the phase 2 and phase 3 trials for faricimab and is now using it as a first-line agent for both diseases.
“In my practice, faricimab has made a clinically meaningful impact in the treatment of patients with nAMD and DME. Faricimab is a strong drying agent and leads to rapid improvements in anatomy. We are able to stabilize/improve vision quickly and then extend treatment intervals up to 16 weeks, leading to decreased treatment burden for our patients,” he said.
In the trials, all AMD patients and the majority of DME patients were treatment naive, and the comparator aflibercept was given every 8 weeks by the label. Therefore, the question of how faricimab compares with aflibercept or other anti-VEGF agents in real-world practice still needs to be answered.
“The only way to know this is to look at the switch data. In the TRUCKEE study that we have recently published, the majority of the patients were previously treated with anti-VEGF, mostly aflibercept. In patients with suboptimal response to the previous treatment, faricimab improved the anatomy after one injection at similar treatment interval and both anatomy and vision after three injections. The drug also performed well in difficult-to-treat naive patients,” Khanani said.
The bispecific nature of faricimab, targeting both VEGF-A and angiopoietin-2 (Ang-2), likely explains the superior drying effect, according to Jennifer I. Lim, MD, another author of the trials.
“When you look at the OCT data, you see better drying with faricimab than with anti-VEGF alone (aflibercept), although visual acuity results are equivalent. That is most likely due to the anti-Ang-2 effect, which contributes to vascular stability and combats leakage as well as inflammation. This improved drying applies to both intraretinal and subretinal fluid. Analysis of the data also shows earlier drying occurring in the faricimab-treated compared with the aflibercept-treated eyes for both AMD and DME,” she said.
Moshfeghi has switched a substantial number of AMD patients and a few DME patients from Eylea (aflibercept, Regeneron) to faricimab. He was consistently less impressed with the outcomes in patients who switched than in treatment-naive patients.
“Some patients have done much better on faricimab, but some have done worse. I never had worse outcomes when I switched patients from Lucentis (ranibizumab, Genentech) to Eylea. In most cases they stayed the same, in some cases they improved, but here with faricimab, 25% to 30% of patients have done worse,” he said.
Khanani hypothesized that Ang-2 may have a delayed effect in some cases. Particularly in DME, while treatment-naive patients respond quickly, patients who switch take some time, he said.
“I think that the Ang-2 part of the molecule takes multiple injections to show efficacy in switch patients. But once it starts, you can see that you can control anatomy better,” he said.
He also believes that a bispecific antibody such as faricimab has advantages over drugs that target only the VEGF-A pathway, but how faricimab will compare with high-dose aflibercept is still to be seen.
High-dose aflibercept
Aflibercept 8 mg, known as Eylea HD (Regeneron), was recently approved by the FDA for the treatment of wet AMD, DME, and diabetic retinopathy. Approval was based on the positive data reported from the phase 3 PULSAR trial for wet AMD and PHOTON trial for DME, with noninferior vision gains for both 12- and 16-week dosing regimens at 48 weeks compared with patients treated with the 8-week dosing. The majority of patients randomly assigned to aflibercept 8 mg in both trials maintained 12- and 16-week dosing regimens during the first year (wet AMD, 79% and 77%; DME, 91% and 89%). The safety profile was similar to the 2 mg formulation, with no cases of retinal vasculitis, occlusive retinitis or endophthalmitis in either trial.
“These data demonstrate that 8 mg aflibercept will be a useful treatment option for patients with the advantage of extended disease control and less frequent injections,” Diana V. Do, MD, principal investigator in the PHOTON trial, said.
One of the benefits of aflibercept 8 mg is that it works with the same mechanism as aflibercept 2 mg, which is well known for its efficacy, she said.
“Aflibercept is a fusion protein that is effective in blocking VEGF-A, which is the main driving force for retinal vascular permeability and neovascularization. In addition, aflibercept also inhibits placental growth factor, which is also implicated in angiogenesis and vascular permeability,” she said.
“Given the positive efficacy and safety data from aflibercept 8 mg clinical trials, I anticipate switching patients who currently are on aflibercept 2 mg to the high-dose aflibercept 8 mg,” Do said. “I’m hopeful that the higher molar dose of aflibercept in the 8 mg formulation will allow for longer intervals of VEGF suppression, allowing patients to have longer periods of disease control and fewer injections.”
The novel formulation delivers 8 mg in 70 µL, while the typical anti-VEGF injection is 50 µL. Lim expressed some concern that this larger volume of liquid might affect IOP.
“I worry about repeated, intermittent pressure elevations related to the injections that may result long term in damage to the nerve fiber layer. I measure IOP immediately after performing an intravitreal injection. Currently, even with the 50 µL dose of various drugs, I detect pressure elevations in some patients. The IOP usually comes down to normal quickly in most patients, although some do have sustained pressures for several minutes. With a larger volume injection, I am concerned that there will be a higher incidence of significant pressure increases and that these higher pressure fluctuations may damage the eye in the long term,” Lim said.
According to Do, the large number of eyes evaluated in the phase 3 trials should be sufficient to dispel this concern.
“There were no differences in IOP rise with the larger dose. I don’t anticipate any safety issues with the volume of aflibercept 8 mg,” she said.
Based on the studies, high-dose aflibercept and faricimab appear to be equal in terms of safety and efficacy, but some specialists may feel more comfortable with high-dose aflibercept because they are familiar with the previous formulation of the drug.
“In some respects, there is an easier threshold barrier to cross. I think that I’m favorably inclined to start using this drug when it becomes available,” Moshfeghi said.
The Port Delivery System
The PDS, short for Port Delivery System with ranibizumab (Genentech), now known as Susvimo, showed efficacy in the phase 3 Archway trial for wet AMD, Pagoda trial for DME and Pavilion trial for diabetic retinopathy. Since its original design, the PDS implant, refill needle and surgical procedures have experienced continued refinements that have lead to reduced frequency of complications. However, more recent cases of septum dislodgement during the refill-exchange procedures led the company to voluntarily recall the device.
“Genentech has undergone an intense investigation, root cause analysis and improvement process, so that the PDS will be available again in the next 6 months to a year,” Dante J. Pieramici, MD, said.
Meanwhile, many of the patients who had the device implanted continue to do well.
“I know that many of my patients who have had the device in one eye and have been getting injections in the other eye are anxiously awaiting to get another device for the other eye now,” he said. “There is a learning curve in the surgical procedure, but surgeons have learned over time how to mitigate complications.”
This, in addition to the device undergoing further manufacturing refinements, should make it possible to bring this option back commercially.
“I think some physicians will be cautious at first, waiting for some longer-term data on safety, but from a patient perspective, the PDS has been really promising. In the real world, it is doing very well in terms of disease control, and many of my patients don’t even need refills every 6 months,” Khanani said.
Six months was the set time of refill in most of the trials, but in Pavilion, the interval was extended to 9 months, and in the phase 2 Ladder trial, 59.4% of patients went 12 months or longer without meeting refill criteria.
Long-term data are being collected in the Portal extension study, following the patients included in Archway and Ladder, as well as in the real-world SUMMIT study.
“Genentech is committed to this program, and they are not going to give up on the PDS. I would hate to abandon such a technology because it delivers very steady levels of drug in the eye, and the pharmacokinetics look great,” Pieramici said.
The benefits of a sustained delivery device go beyond the here and now, he said.
“This is a platform therapy, which means that it is used right now to deliver ranibizumab, but in the future, it could be refilled with various molecules,” he said. “From an extended delivery standpoint, very few will be able to match it — perhaps gene therapy, but this still has a lot of unknowns in terms of safety and cannot be reversed.”
Brolucizumab and steroids
Beovu (brolucizumab, Novartis) showed favorable outcomes in the HAWK and HARRIER studies, but safety issues have severely limited its use in clinical practice.
“Brolucizumab has a higher rate of intraocular inflammation than other anti-VEGF agents, and it has been associated with retinal vasculitis and retinal artery occlusion. The risks outweigh the benefits, and I am not using it in my patients,” Do said.
Because safer options are available, the majority of retina specialists are not using it.
“I don’t have a single patient on it anymore, and I have switched all patients I had to faricimab,” Khanani said.
Corticosteroids still have a place in the treatment of DME for patients who have incomplete or limited response to anti-VEGF therapy, according to Pieramici.
“It’s infrequent because 90% to 95% of my patients with DME are on anti-VEGF injections, but maybe 5% or 10% of the time we have gone to something like Ozurdex (dexamethasone intravitreal implant, Allergan), and there are new sustained-delivery suprachoroidal implants underway,” he said.
Lim would only use steroids in the rare cases in which anti-VEGFs are contraindicated, such as after a recent heart attack, severe DME during pregnancy or chronic DME.
“I am a very low steroid user, and I have always been because of the side effects. The anti-VEGFs typically work well, and despite the higher treatment burden, patients prefer to receive anti-VEGF injections because they typically have good vision and do not want to risk pressure problems or cataract formation,” she said.
Pragmatic, personalized regimens
Treat and extend (T&E) is the single most popular paradigm for treating all retinal vascular disease patients with anti-VEGF therapy. It is also the safest extrapolation of available clinical trial data because it has back steps in case the extension fails, according to Moshfeghi.
“One failed extension is not the end of the world. You just treat the patient again and make the next interval shorter,” he said.
With T&E, it is the art of medicine to guide the physician rather than the algorithms of the studies.
“We prefer a more flexible, custom-made therapy tailored to the individual patient based upon their baseline vision, their initial response and how long it takes them to get dry. There are many variables that don’t fit with the rigid and arbitrary schedules of the studies,” Moshfeghi said. “With whatever drug, I initially extend by 1 or 2 weeks, mostly 2 weeks, and see if I can be more generous later.”
Trial criteria, he said, are not easy to explain to patients, who hear on TV commercials about treatments that are administered every 4 months and expect this to be available straight away.
“Patients come into my office asking for these new drugs and say, ‘I want you to give me a Vabysmo today, and then I’ll come back in 4 months,’” Moshfeghi said. “So, that is my take on the studies. While innovative, they do not represent an easily digestible set of data that patients can relate to.”
Unmet needs and challenges
Despite progress, there are still unmet needs and challenges ahead. For DME patients, duration is a key aspect.
“It’s hard for patients with DME to come every 3 or even 4 months. They are working patients, or if they are not, they have comorbidities that may contribute to lost to follow-up,” Lim said.
Also, no treatment so far has been able to address ischemia.
“With anti-VEGFs, we are ‘mopping up’ fluid that leaks out of vessels as a result of ischemia. We are not addressing the actual pathology and the pericyte loss. With faricimab, we have made some progress in that direction, but we definitely need to look into other novel mechanisms of action with different drugs,” she said.
In AMD, the next goal is a treatment that can prevent retinal pigment epithelium (RPE) atrophy. Pegcetacoplan and avacincaptad pegol have shown the ability to slow down progression of atrophy in some patients with dry AMD. Unfortunately, these drugs harbor a small but real increased rate of conversion to wet AMD, according to Lim.
“Even a 5% to 10% chance of developing wet AMD is not acceptable to the majority of my geographic atrophy patients,” she said. “The ideal treatment goals would be prevention of photoreceptor death, photoreceptor rescue, RPE regeneration and prevention of fibrosis.”
“The No. 1 unmet need is still duration of action in a consistent manner for upwards of 90% of patients,” Moshfeghi said.
Although a greater proportion of patients can be treated with an interval of 3 to 4 months, it is not yet possible to identify those patients a priori.
“You cannot confidently say to every new patient, ‘You start on these drugs, and you are going to need re-treatment only every 3 to 4 months after the loading dose.’ You can tell them they have a 75% to 80% chance of that occurring. What we need is a drug that does what these drugs do with monthly dosing, where 95% of patients are dry with stable or improved vision. With monthly dosing, that’s consistent for almost every patient. It should be that way for whatever duration we’re looking for,” he said.
Click here to read the Point/Counter to this Cover Story.
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- For more information:
- Diana V. Do, MD, of Byers Eye Institute, Stanford University, can be reached at dianado@stanford.edu.
- Arshad M. Khanani, MD, MA, of Sierra Eye Associates in Reno, Nevada, can be reached at arshad.khanani@gmail.com.
- Jennifer I. Lim, MD, of the University of Illinois at Chicago, can be reached at jennylim@uic.edu.
- Andrew A. Moshfeghi, MD, MBA, of USC Roski Eye Institute, Keck School of Medicine, can be reached at amoshfeghi@gmail.com.
- Dante J. Pieramici, MD, of California Retina Consultants, can be reached at dpieramici@yahoo.com.
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