Sustained anti-VEGF therapy: Pros and cons of the PDS for treating retinal disease

(Image credit: ©Aliaksandr Marko/AdobeStock)

Yasha Modi, MD, from NYU Langone Health, New York, New York, and Carl Danzig, MD, from the Rand Eye Institute, Deerfield Beach, Florida, participated in an opinion panel for Modern Retina. They discussed the clinical benefits, clinical trial results, surgical considerations, and factors affecting clinician decision-making regarding the Port Delivery System (PDS) with ranibizumab injection (Susvimo; Genentech) in clinical practice.

The PDS with ranibizumab got off to a slightly rocky start with reports of dislodgement of the device, but its track record smoothed out with modifications to the septum and needle. The availability of the PDS device alleviates the patient burden requiring the frequent need for anti-VEGF injections, office visits, and the anxiety associated with injections. Few patients can achieve treatment intervals with intravitreal injections that extend out to
16 weeks, according to Danzig.

The PDS is implanted into the eye, so that it protrudes into the vitreous cavity to provide passive diffusion of drug molecules through a filter into the eye, resulting in a constant bathing of the vitreous with ranibizumab, Danzig explained. The device’s reservoir can be refilled roughly every 6 months or longer in some patients. The phase 3 Archway trial (NCT03677934) showed that more than 98% of patients did not need a supplemental injection of ranibizumab, in contrast to the average of 23 injections administered before entry into the study, Modi pointed out. Echoing this, Danzig said, “This 1-year percentage is phenomenal.”

Adverse effects of the PDS

Danzig and Modi discussed how PDS implantation requires careful patient selection and meticulous surgical technique to minimize complications that include vitreous hemorrhage and endophthalmitis. Factors such as active inflammation, a thin sclera, or the presence of glaucoma filtering devices are contraindications to implantation of the device.

Danzig emphasized the importance of addressing adverse effects preoperatively with patients. Conjunctival erosion and endophthalmitis are complications, the latter of which developed in 1.6% to 2% of cases at 3 years, likely because of conjunctival erosion. Septum dislodgement occurred early but was resolved with a redesign of the device; conjunctival blebs and transient vitreous hemorrhages are other potential adverse effects.

Related viewing: Tyrosine Kinase Inhibitors to Prolong Efficacy of Anti-VEGF Therapies

He advised paying particular attention to the incision because of the potential for vitreous hemorrhage closure by lasering the area around the incision. At the end of the case, he also advised that surgeons ascertain adequate wound closure.

Modi recommended using the sizer in the PDS kit to make the incision to ensure the proper wound size. He uses a 25-gauge microvitreoretinal blade to cut down and dissect the tissue to reach the suprachoroidal space. He then applies endolaser to cauterize the depth of the incision and uses a blade to make a single pass into and out of the eye with no side-to-side movement to avoid nicking the choroidal vessels.

The PDS is then implanted using its injector. Because the device is embedded, there is no need for a suture to secure the implant to the sclera. In this case, to prevent conjunctival retraction, a key point is to close at the limbus and drag and bring up the Tenon capsule to the limbus. “The result is a Tenon layer and a conjunctival layer to prevent erosion,” Modi stated. He also emphasized strongly that surgeons cannot concentrate only on the retina and optical coherence tomography images; the conjunctiva must be studied for early signs of erosion. If erosion is observed, the patient must return to the operating room to avoid the development of endophthalmitis. Patients are warned to avoid eye rubbing and potential consequent erosion and infection.

Candidates for PDS implantation

The biggest challenge that Danzig faces in his practice is the unwillingness of patients to undergo a surgical procedure because they erroneously equate a retinal surgery with the need to remain face-down postoperatively, he shared. He explains to patients that the availability of the PDS is an opportunity to have an effective, long-term solution that provides continuous medication without the frequent office visits for anti-VEGF injections.

A consideration for some patients with comorbidities may be the need to stop anticoagulant therapy. Modi prefers that patients remain on that medication and perhaps develop a vitreous hemorrhage rather than run risk a stroke from atrial fibrillation.

PDS surgical learning curve

The panelists discussed the importance of implanting the PDS in a sterile operating room, as in the clinical trials. Modi pointed out that changes in the procedure may occur but advised surgeons during their early experience with the PDS implantation to reach out to Genentech for assistance with the surgeries to achieve the outcomes reported in the trials. His concern was the avoidance of vitreous hemorrhages.

A surgical liaison in the operating room as a coach may ensure better surgical outcomes. He advised, “Watch Genentech’s surgical videos, be fully aware of all the surgical steps, and refer to them in the operating room. This will avoid poor outcomes in the learning curve.”

Refilling the PDS: Some pearls

Refilling the device requires attention to detail; there can be no air bubbles in the medication when drawing it into the specialized needle used for implantation. “This is a foreign body in the eye, and the body’s natural response is to encapsulate it. In addition to conjunctival blebs, a thick capsular plaque can develop; this occurs more often in younger diabetic patients than in those with age-related macular degeneration,” Modi said.

In addition, during the refilling procedure, the opening in the device where the needle is inserted can be difficult to see. To work around this, he has an assistant hold a flashlight to the side for better visualization.

Unlike administering an intraocular injection, he always uses a lid speculum when filling the PDS. During this procedure, he uses a cotton swab to stabilize the eye and positions the needle perpendicular to the center of the implant. “When the needle is not perpendicular, the septum can be damaged as the result of pushing against the rubber stopper that, in turn, can damage the implant,” Modi described. If damage occurs and the medication is injected, it does not diffuse properly in the eye.

He also warned that if multiple attempts are made to fill the PDS, the conjunctiva can bleed, and the landmarks are lost, which results in postponing the refilling of the device. He opined that the refill stage likely resulted in the problematic septum dislodgment in the first-generation PDS. Genentech is conducting a study for patients with septum dislodgement that provides an opportunity to remove and replace the PDS.

Tyrosine kinase inhibitors: Potential competitors to the PDS

These medications (axitinib [Axpaxli; Ocular Therapeutix] and vorolanib [Duravyu; EyePoint Pharmaceuticals]), which are in clinical trials, may be an alternative approach to reducing the injection burden of anti-VEGF drugs while potentially offering broader therapeutic effects. Danzig thinks the efficacy of these medications will not be as high as that achieved with some patients implanted with the PDS. “However, I think that the TKIs [tyrosine kinase inhibitors] will have an excellent safety profile, which we are acutely aware of in the retina subspecialty,” he commented.

Although the problems with the first-generation PDS have been ironed out, endophthalmitis remains a concern with implants. The TKIs consist of a vehicle (shell) and the medications. One of the TKIs, axitinib, is not pegylated (ie, the shell matrix is pegylated but it is not conjugated to the medication), according to Danzig, and there is no immunogenicity involved.

Modi noted that the TKIs are bioerodible devices without hardware. “There is no perpetual hardware risk. We have learned from glaucoma devices that include tubes that there is a risk of endophthalmitis at the time of implantation, but also much later down the line with erosion,” he said.