Source: Healio Interviews
Disclosures: Baumal reports she is a speaker for Genentech and Novartis and does research for Genentech, Novartis and Ocular Therapeutix. Campochiaro reports he is an advisory board member for Genentech. Khanani reports he is a consultant for Genentech, Regenxbio and Adverum Biotechnologies. Kiss reports he is a consultant for Genentech and a consultant and equity holder for Regenxbio and Adverum Biotechnologies. Singer reports no relevant financial disclosures.
September 22, 2020
12 min read
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Strategies for sustained anti-VEGF delivery aimed at consistent dosing, durability

Source: Healio Interviews
Disclosures: Baumal reports she is a speaker for Genentech and Novartis and does research for Genentech, Novartis and Ocular Therapeutix. Campochiaro reports he is an advisory board member for Genentech. Khanani reports he is a consultant for Genentech, Regenxbio and Adverum Biotechnologies. Kiss reports he is a consultant for Genentech and a consultant and equity holder for Regenxbio and Adverum Biotechnologies. Singer reports no relevant financial disclosures.
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Durable treatment options that ensure consistent treatment outcomes and reduce the burden of multiple injections are an unmet need for neovascular age-related macular degeneration and other retinal vascular diseases treated with anti-VEGFs.

Looking at a large database of 98,821 eyes, the SIERRA-AMD real-world evidence study confirmed what other similar studies found previously: The treatment burden leads to missed visits and decreased injection frequency, with consequent gradual decline in visual acuity over time.

“The biggest unmet need in patients with neovascular age-related macular degeneration is durability. We need sustained anti-VEGF delivery systems to improve compliance and preserve or improve long-term vision in routine clinical practice,” Arshad M. Khanani, MD, MA, first author of the study, said.

Caroline R. Baumal, MD
Caroline R Baumal, MD, expects high-resolution imaging technologies, home-based devices and machine learning to play a crucial role in advanced retinal treatments.

Source: Caroline R. Baumal, MD

Pursuing this goal with retinal therapies has become even more of a priority in the context of the pandemic.

“The COVID-19 pandemic has shown us how vulnerable our patients are. Many have been fearful to go to an office to seek treatment during this time. In some countries, the ability to obtain intravitreal injections may have been prohibited by restrictions, lack of transport or office closures. So, more now than ever, durability and maximizing vision outcomes are the two goals for companies and doctors,” Caroline R. Baumal, MD, said.

On the other hand, when properly administered in a timely manner, injections are effective, deliver the required dose of medication directly to the target and have a low-risk profile.

“We may want to move to a different mode of drug delivery, but it would have to be as safe as intravitreal injections,” Baumal said.

Port Delivery System

Drug depots and gene therapy are two promising pathways that show strong potential in managing current unmet needs in sustained delivery.

The Port Delivery System (PDS, Genentech) is a refillable reservoir that is implanted through the pars plana and slowly releases ranibizumab into the vitreous cavity.

“There is a constant low-level release of the drug that results in a therapeutic level for many months,” Peter A. Campochiaro, MD, said.

In the phase 2 LADDER and phase 3 Archway studies, the PDS was generally well tolerated and achieved visual acuity outcomes comparable to monthly intravitreal ranibizumab injections in the treatment of neovascular AMD.

Peter A. Campochiaro, MD
Peter A. Campochiaro

“It gives equal efficacy to monthly injections with much less treatment burden. Particularly important, it is quite predictable. In Archway, 98% of the patients who had the PDS did not require a supplemental injection prior to the first refill exchange. In clinical practice, this means that we may want to see the patient a couple of times over the first 6 months to make sure that there are no complications and that the patient does hit the target for duration. After that, patients will be able to return every 6 months to have a refill exchange. This will result in huge time saving, easier management for the physician and less burden for the patient,” Campochiaro said

Implantation and refill exchange

In the first part of the LADDER trial, there was a 50% rate of vitreous hemorrhage, which resulted in a modification of the PDS implantation technique. The new protocol incorporated laser photocoagulation to the pars plana at the incision site to cauterize the blood vessels, leading to a 10-fold reduction of this complication.

“We now perform a partial-thickness incision through the sclera, expose the pars plana, treat it with laser, and then make the incision through the pars plana into the vitreous and insert the PDS. The same technique was replicated in Archway, where only 5.4% of PDS patients had vitreous hemorrhage that cleared spontaneously without vitrectomy,” Campochiaro said.

Refilling is performed in the office, with a custom refill-exchange needle inserted perpendicularly through the conjunctiva and the center of the underlying implant septum.

“When you push down on the plunger, fresh ranibizumab is injected and the old residual liquid is evacuated. It is an exchange procedure, very easy, well tolerated by patients who experience less discomfort than with a regular intravitreal injection,” Campochiaro said. “There is a learning curve. The main thing is to identify exactly where that septum is by making the patient look down and nasally. Get the center of the septum and apply more pressure there because the septum has more resistance than the sclera. Warn patients that they are going to feel more pressure on the eye but less pain. After you have done this once or twice, patients get well adjusted to it, and it is not a problem.”

Any new surgical procedure potentially has complications, but gradually the surgeon learns to identify and manage the critical steps that need attention. With the PDS, the size of the incision needs to have a specific dimension.

“Initially, it was between 3.5 mm and 3.7 mm, but we found that some investigators went slightly above 3.7 mm, causing instability of the PDS. In one instance, the PDS dislocated into the eye at the first refill exchange. Therefore, the protocol was modified to make sure the incision was exactly 3.5 mm. If it is longer, put in a suture at one of the borders to achieve the correct size,” Campochiaro said.

Another critical step is conjunctival closure because a conjunctival defect due to retraction or erosion can be a source for infection.

“When you open the conjunctiva, dissect it right at the surface of the sclera to leave the Tenon’s capsule adherent to it. Then close over the septum with both Tenon’s capsule and conjunctiva and secure it with episcleral bites at the limbus, making it quite tight, with the edge overlapping a bit of the peripheral cornea. In this way, when it retracts, because there is always a tendency to retract, it retracts to the limbus, which is where we want the edge of the conjunctiva to be,” Campochiaro said.

A welcome change

From his own experience, Campochiaro learned that results can be remarkable.

“The disease becomes quite quiescent, the patient comes back, and sometimes it is difficult to tell they have wet AMD. You see the signs of dry AMD but very little in terms of disease activity,” he said.

Importantly, patients are happy, and patient-reported outcomes show that 93% prefer the PDS to monthly injections.

“This is a change that patients will embrace. Those who have bilateral disease and PDS in one eye are constantly asking when they can have it in the other eye instead of injections,” Campochiaro said.

The long-term outcomes of PDS are being investigated in the Portal extension study, which includes all patients from LADDER and Archway. The aim is to provide long-term safety and efficacy data. It will also allow the study participants to continue receiving treatment until approval is obtained, possibly in the second quarter of next year.

“With Portal, we are beginning to explore whether a constant delivery provides better outcomes in the long term. With injections, there are ups and downs, and there is a period when patients are undercovered, particularly when you use [treat and extend] rather than monthly injection, which is what most people do in clinical care,” Campochiaro said.

A constant low-level suppression of the disease is likely to be better in terms of long-term outcomes, he said.

Burden relief in DME

The PDS is also undergoing evaluation in patients with diabetic macular edema in the phase 3 Pagoda study.

“Enrollment should be completed by the end of this year, and we’ll have results maybe 9 months after that. We do know that the vast majority of DME patients, particularly at the early stages of the disease, are responsive to anti-VEGF, and this trial will tell us if response can be as outstanding as it is for AMD with sustained delivery,” Campochiaro said.

If a switch to or combination with steroids is required, the implant can remain in place and be refilled as needed.

This method will be valuable for DME or diabetic retinopathy, according to Baumal, because those patients have greater compliance issues.

“Patients with diabetes are usually younger and have multiple other medical issues, complications and appointments with a variety of specialists that time management can be quite overwhelming. They often miss visits and injections and are therefore at a high risk of long-term vision loss,” she said.

The one-time implantation in the OR followed by refill every 6 months in the office would make a notable change in the lives of many patients.

“Ideally, it could be complemented by OCT monitoring at home in the near future, which would allow more individualized care because it would signal if patients need to have the port refilled. Patients who don’t need to be refilled every 6 months could have the treatment tailored to their needs. That is something that I hope will be in our hands soon,” Baumal said.

Bioresorbable OTX-TKI implant

The OTX-TKI (Ocular Therapeutix) is a bioresorbable hydrogel fiber implant with anti-angiogenic properties delivered via intravitreal injection using a 27- to 30-gauge needle.

“It was designed with a target duration of release for 6 to 9 months and is meant to treat patients with wet AMD and other retinal diseases. It provides sustained-release tyrosine kinase inhibitor (TKI), a drug that acts directly on VEGF receptors and therefore may have broader anti-angiogenic properties,” Michael A. Singer, MD, said.

Preclinical data have demonstrated the ability to deliver therapeutic dose of TKI to the posterior segment of the eye for the treatment of VEGF-induced retinal leakage for an extended duration of up to 12 months with a single injection. A multicenter, open-label phase 1 clinical trial is underway to evaluate the safety, durability and tolerability of OTX-TKI. Interim data of two cohorts treated with different doses showed a favorable safety profile.

“Preliminary signs of biological activity were observed in the higher-dose group, demonstrated by a decrease in intraretinal and subretinal fluid starting at 2 months and durability of therapy for up to 4.5 to 6 months in some subjects with wet AMD. Additionally, some subjects in cohort 1 who required frequent anti-VEGF dosing prior to enrollment in this study were shown to not need rescue therapy for as long as 10 months after being treated with OTX-TKI,” Singer said.

The company is working on a suprachoroidal aflibercept delivery program with Regeneron, called OTX-AFS, currently in preclinical stages of investigation.

“Suprachoroidal in theory should lead to increased efficacy and durability, with potentially higher concentration of the drug,” Singer said.

One-time RGX-314 treatment

Gene therapy holds the promise of a one-time treatment that reprograms the DNA of target cells to fight disease. In the case of neovascular AMD, cells are instructed to produce specific anti-VEGF proteins.

“There is a potential that gene therapy can actually lead to sustained protein production by making the eye become a biofactory for anti-VEGF production,” Khanani said.

Arshad M. Khanani, MD, MA
Arshad M. Khanani

RGX-314 (Regenxbio) uses a novel adeno-associated virus serotype 8 (AAV8) vector that holds a gene encoding for anti-VEGF Fab, similar to ranibizumab. It is injected subretinally in the OR after vitrectomy using a small-gauge cannula. The current phase 1/2a dose-escalation trial is evaluating 42 patients across five cohorts, and at this stage, the treatment appears to be safe, with no serious adverse events, most of which are associated with the surgical procedure.

“In terms of efficacy, we have 2-year data for the first three cohorts, and what we have seen is that patients are maintaining or improving vision with stable OCT anatomy. In cohort 3, patients gained 14 letters by the end of 2 years. Half of the patients in cohort 3 did not require a rescue injection, which is great news for durability. In cohort 4 and 5, we have 6-month data showing patients have stable or improved vision and anatomy, and 73% of patients in cohort 5 have gone without a rescue injection until 9 months,” Khanani said. Khanani presented data for RGX-314 at the virtual American Society of Retina Specialists meeting in July.

RGX-314 protein levels showed a dose-dependent, continuous, stable protein production at 6 months, 12 months and 2 years.

“An alternative approach to surgical delivery in the OR is in-clinic suprachoroidal delivery, which is currently being studied. If the safety and efficacy of the approach is acceptable, this would allow us to provide this treatment option to a larger number of patients,” Khanani said.

ADVM-022 injectable gene therapy

ADVM-022 (Adverum Biotechnologies) is another gene therapy that is injected in the office with the same procedure used for standard anti-VEGF therapies.

“We reverse-engineered the aflibercept molecule and put the genetic code for aflibercept into a novel vector capsid, a modified AAV2 capsid called AAV.7m8, able to cross the internal limiting membrane to transfect retinal cells. What ADVM-022 produces is similar to the aflibercept that you buy off the shelves, in an amount equivalent to the levels approximately 25 days after a single bolus injection with the commercially available product,” Szilárd Kiss, MD, said.

This quantity is achieved at around day 20 to 25 and maintained at a constant level thereafter.

Szilárd Kiss, MD
Szilárd Kiss

The OPTIC phase 1 multicenter, dose-escalation prospective trial is currently evaluating the safety and tolerability of a single administration of ADVM-022 in patients with neovascular AMD who are responsive to anti-VEGF treatment. With a median of 72 weeks of follow-up, the first cohort of patients, who on average needed injections every 6 weeks, did not need any rescue injections and showed an improvement in OCT thickness of –21 µm and an improvement of vision of two ETDRS letters. In the higher-dose cohort 1 patients, there was a 100% reduction in annualized anti-VEGF injection rate; in the lower-dose cohorts 2 and 3, there was an 87% reduction.

“There is no free lunch, so there was some inflammation occurring in some of the patients treated with ADVM-022, typically mild and not involving the retina. It is not a vasculitis, choroiditis or retinitis like the inflammation noted with brolucizumab or abicipar. The inflammation with ADVM-022 manifests typically as anterior chamber cells with some vitreous spillover. Importantly, data from cohorts 3 and 4 indicate that topical steroid drops can be effective in controlling this inflammation,” Kiss said.

ADVM-022 is now also being studied in a phase 2 prospective multicenter clinical trial in patients with diabetic macular edema (INFINITY trial), he said. Unlike the OPTIC trial, INFINITY is masked and has an active comparator of aflibercept.

Bright future

“Every pharmaceutical company is trying to develop a therapy with longer duration of action because studies have shown that over time patients get less injections, and it is not possible to reproduce the results of phase 3 trials,” Baumal said.

She expects reservoirs to be available sooner than other innovations because they are further on in the phases of studies and use drugs that have already proven their safety and efficacy. Gene therapy results are promising, but long-term safety data are needed.

“We know from Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics) that the eye is the perfect site for gene therapy, and patients have had long-term effects on vision,” Baumal said. “We expect gene therapy for AMD and other retinal diseases to be coming our way within the next decade, maybe sooner.”

For these advanced therapies, Baumal expects that high-resolution imaging technologies, home-based devices and machine learning will play a crucial role in better identifying and monitoring patients for timely, personalized treatment.

“The future is very bright for our patients with retinal diseases because we have so many molecules and delivery systems in the pipeline, and they look promising. We need our patients to reach the goal of maintaining vision gains with AMD, diabetic retinopathy and retinal vein occlusion, and these options will be a great addition to our toolbox to help these patients do well,” Khanani said.

Click here to read the Point/Counter to this Cover Story.