Relieving the burden

New approaches to AMD focused on reducing burden of treatment

Dermot McGrath

Posted: Wednesday, September 2, 2020

With regular intravitreal injections still the norm, treatment burden has become the critical issue in neovascular AMD care. Physicians are now focused on finding effective strategies to extend the dosing interval, avoid under-treatment and maximise visual acuity gains.

“Anti-VEGF agents such as ranibizumab (Lucentis), bevacizumab (Avastin) and aflibercept (Eylea) work very well and are the gold standard, but we need drugs that work longer and have the same efficacy and hopefully even better anatomic results,” said Peter K Kaiser MD, Professor of Ophthalmology at Cleveland Clinic Lerner College of Medicine in Ohio, United States, during a special session on AMD at the World Ophthalmology Congress 2020 Virtual.

Dr Kaiser emphasised the need to reduce the treatment burden for patients and ideally have long-term visual gain.

“A lot of our real-world studies with anti-VEGF agents show that the results are not as good as in the clinical studies where there is more aggressive treatment. The hope for new agents and other approaches currently under development is that we can more closely match the clinical trial results in the real world,” he added.

Any new anti-VEGF treatment hoping to make an impact on the market will need to show similar safety, efficacy and durability to aflibercept which has already been approved by the FDA for four-, eight- and 12-week dosing schedules.

Recently approved by the US FDA, Brolucizumab (Beovu, Novartis) demonstrated superior anatomic outcomes and non-inferior best-corrected visual acuity (BCVA) at eight to 12-week dosing intervals compared with aflibercept dosed every eight weeks in clinical trials. However, concerns about the drug’s safety profile surfaced in the wake of reported cases of retinal vasculitis after brolucizumab injections. A Novartis safety review subsequently found retinal vasculitis, retinal artery occlusion or severe vision loss occurred in 8.75-to-10.08 out of 10,000 injections. Several national regulatory agencies, including the FDA, have subsequently updated their prescribing information (PI) to include
these new vision-related side effects.

Abicipar pegol (Allergan/Molecular Partners) is another new drug that successfully extended dosing intervals up to around 12 weeks without loss of efficacy in phase III trials compared to monthly ranibizumab. However, as with brolucizumab, concerns have been raised about the drug’s safety profile, with a high rate of intraocular inflammation (up to 15.3% in the CEDAR and SEQUOIA studies) following abicipar injections compared to almost zero rates with ranibizumab and other anti-VEGF agents. Citing an unfavourable benefit-risk ratio, at the end of June 2020 the FDA declined to approve abicipar pegol for treatment of nAMD.

Conbercept (Kanghong Biotech), an anti-VEGF recombinant fusion protein that was approved in China in 2013, is currently undergoing worldwide, randomised clinical trials (PANDA) to evaluate its efficacy and safety of conbercept delivered every 12 weeks compared to aflibercept every eight weeks in treating nAMD. In earlier trials, a quarterly dosing schedule with conbercept 0.5mg was shown to be effective at maintaining visual acuity gains.

Faricimab (Genentech), a drug that inhibits angiopoietin 2 (Ang2) as well as anti-VEGF A subforms, has shown solid efficacy at 12-to-16 week treatment intervals as opposed to monthly ranibizumab in phase II trials. The drug is currently in phase III trials with patients randomised to receive either faricimab every 12-to-16 weeks or aflibercept dosed every eight weeks.

KSI-301 (Kodiak Bioscience), a large molecule antibody-biopolymer conjugate with an anti-VEGF A antibody with Lucentis-like binding domains, may also provide an important dosing advantage compared to existing anti-VEGF drugs. Initial results from the phase II DAZZLE study underscored the potential of the drug to extend dosing schedules, with 84% of wet AMD eyes and 76% of DME eyes extended to four months or longer after the last loading doses before receiving their first retreatment.

A potentially major disruption to the current nAMD treatment landscape may soon arrive in the form of biosimilars, a biologic medical product highly similar to an already approved biological medicine.

With the patents on Lucentis expiring in the US in 2020 and in Europe in 2022, a number of ranibizumab biosimilars are already in the pipeline. One such biosimilar, Razumab (Intas Pharmaceuticals Ltd), has been approved for clinical use in India since 2015 for all the indications in which ranibizumab is used. Others such as FYB 201 (Formycon AG) and Xlucane (Xbrane Biopharma) are expected to obtain approval for the US market this year.

Other biosimilars for aflibercept are expected to obtain approval before 2025 in Europe and the US once the patent for aflibercept expires in those regions.

Some manufacturers are turning to new delivery systems to potentially ease the treatment burden. Currently undergoing phase III trials, Graybug Vision’s GB-102 injectable microparticle technology delivers sustained release of the tyrosine kinase inhibitor, sunitinib malate. The randomised study will compare 1mg and 2mg doses of GB-102 administered every six months to aflibercept every two months.

Another approach has been embraced by the Port Delivery System (PDS, Genentech). Currently in phase III clinical trials, the PDS is a surgically implanted, refillable intraocular implant that can be filled with a customised formulation of ranibizumab. The implant is placed surgically at the pars plana and can be refilled in the office.

In the phase II LADDER trial, 80% of the patients in the 100mg highest dosage group went greater than or equal to six months without requiring a PDS refill and achieved similar BCVA gains and reductions in central retina thickness to those receiving ranibizumab 0.5mg injections.

The Archway trial met its primary endpoint at 40 weeks, and the PDS with refills every six months provided equivalent visual and anatomical outcomes to monthly ranibizumab injections, while reducing the treatment burden fivefold.

Although the results from the clinical trials were promising, the device may not be suitable for all patients, according to Dante Pieramici MD, one of the study investigators.

“It is a surgical procedure and people will look at some of the complications such as endophthalmitis which may be higher than with intravitreal injections, so we are going to have to balance those issues for our patients.

“A patient who is doing very well on anti-VEGF and needs an injection every eight-to-12 weeks may not be so enthusiastic about the PDS. On the other hand, a patient who needs the drug every four-to-six weeks and has tried different agents may be a lot more enthusiastic about it,” he said.

Gene therapy could transpire to be the real game-changer in nAMD treatment in the next few years, delivering a durable “once and done” alternative to regular intravitreal injections.

The concept is to use a viral vector to deliver an anti-VEGF gene into a patient’s own DNA. The gene then produces its own therapeutic anti-VEGF protein without the need for ongoing injections.

Initial trials of therapies such as ADVM-022 (Adverum) and RGX-314 (RegenexBio) have shown promise for the treatment of exudative AMD.

In phase I trials, ADVM-022 was found to be safe and well tolerated and showed consistent and sustained anatomic improvements in OCT and stable best-corrected visual acuity. No rescue injections were required up to one year in cohort 1.

RGX-314 has completed phase I/IIa trials in 42 wet AMD patients with five dosing cohorts. After a single subretinal injection, 50% of patients (3/6) in dosing cohort 3 remain anti-VEGF injection-free over two years, and 67% of patients (4/6) are anti-VEGF injection-free from nine months to two years.

“RGX-314 appears to be well tolerated at all dose levels and in this trial we saw no significant inflammation. The gene therapy has long-term durable treatment effect demonstrated over two years, with improved visual acuity and stable retinal thickness,” said Allen C. Ho MD, of Wills Eye Hospital, Philadelphia, United States, speaking at the World Ophthalmology Congress 2020 Virtual.

Dr Ho said the next trials would examine the safety and efficacy of suprachoroidal delivery of the gene.

“Gene therapy is moving forward and it is very exciting for our patients – the science is very compelling and there is a lot more to come,” he said.