Intravitreal anti–vascular endothelial growth factor (VEGF) therapies have allowed many patients with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) to achieve improved or stabilized vision. Anti-VEGF injection frequency has been linked to the achievement of long-term visual acuity gain in multiple real-world studies.¹ However, it can be difficult for patients to receive frequent injections and monitoring, and undertreatment can contribute to long-term visual decline, especially in patients with nAMD.^2-4 Treatment strategies that can achieve the clinical benefits of regular intravitreal anti-VEGF therapy, while reducing the overall treatment and office visit burden, are therefore needed to improve patient outcomes.

Susvimo (Genentech), commonly known as the Port Delivery System (PDS), is a surgically implanted, innovative, long-acting drug delivery device that provides the continuous release of ranibizumab into the vitreous. The FDA approved the PDS in October 2021 for treating nAMD, with further studies examining PDS for the treatment of patients with DME and diabetic retinopathy (DR).^5-8

THE IMPLANT AND REFILL PROCEDURE

The PDS is surgically implanted through a small incision in the sclera and pars plana in the operating room under local anesthesia.^8-10 A 25- or 27-gauge infusion cannula is placed in the inferotemporal quadrant, and the infusion is left off. To improve visualization, a 7-0 vicryl traction suture can be placed at the limbus superiorly. A 6mm x 6mm superotemporal conjunctival peritomy is performed with non-toothed forceps and Westcott scissors, with undermining of the conjunctiva and Tenon’s capsule in order to provide proper laxity for future conjunctival closure. Cautery is used for hemostasis. The implant is then slowly filled with ranibizumab using the microscope for visualization, ensuring that no air bubbles greater than a third of the diameter of the implant are present.

A small dome of drug should be present at the top of the implant by the end of the fill. Excess fluid is removed from the surgical field so that fixed, marked calipers can be used to mark the 3.5-mm scleral incision, 4 mm posterior to the limbus. An MVR blade is used to make a 3.5-mm scleral incision, exposing the choroid. The 3.5-mm caliper is used to reconfirm the scleral incision length. Laser is then applied to the choroid with a 25- or 27-gauge laser probe, applying overlapping long duration, 1000-ms burns to thin the choroid.

Special attention should be given to the corners of the incision, which are the most likely areas to bleed and cause postoperative vitreous hemorrhage. Laser application should be limited to the choroid, avoiding laser burns to the sclera to decrease the likelihood of wound distortion. The endpoint of the laser is thinning, greying and bubbling of the choroid, with possible vitreous fluid egress. The scleral wound should be remeasured when laser is concluded; if the wound is larger than 3.5 mm, 8-0 nylon suture should be used to decrease the size of the scleral incision to 3.5 mm. The choroid is then entered slowly with the 3.2-mm slit knife, taking care to not touch the corners of the incision.

If there is any hemorrhage at the corners of the incision, fine tip diathermy should be used for hemostasis. The prepared PDS implant should then be inserted into the sclerotomy. If there is any vitreous prolapse, the vitreous cutter can be used to trim excess vitreous from around the implant. The infusion can also be turned on if necessary. The conjunctiva and Tenon’s capsule are then carefully closed over the implant, with an anchoring 3-1-1 suture at the limbus.

Incorporating a scleral bite and making this anchoring suture more anterior so that there is a little bit of limbal overhang will decrease the chance of conjunctival retraction. Using 8-0 nylon suture on a non-cutting BV needle, with non-toothed forceps will also decrease the risk of conjunctival trauma. Sutures directly overlying the implant will increase the risk of conjunctival erosion and should be avoided.

The device is refilled in the office every 6 months with 0.1 mL of a specially formulated 100-mg/mL ranibizumab using specifically designed dual bore 34-gauge refill needles.⁵ Refills in office require the usage of sterile gloves and sterile technique but can be performed with task lighting, loupes and topical anesthesia. The patient should be lying as flat as possible, and for best visualization, the chair should be raised as high as possible.

After placing the lid speculum and a drop of antiseptic on the implant, sterile technique should be used to withdraw the drug from the vial, which is held by a clinical assistant. The refill needle is placed on the syringe, and the amount of drug is purged to 0.1 ml, taking care that no air bubbles remain in the syringe. Standing on the contralateral side of the implant, the globe is stabilized with a cotton swab. The refill needle is perpendicularly targeted towards the center of the septum. If the needle is in the correct location in the correct orientation, it should glide in easily at first, then the needle will meet a little resistance until it goes through the septum.

Fibrosis over the implant or hemorrhage can sometimes obscure septum visualization. Retroillumination can be helpful in these cases to identify the location of the center of the septum. If the refill needle bends or there is initial resistance, the needle may not be in the correct location or may not be entering the implant in a perpendicular fashion. The needle should be withdrawn and reoriented for another refill attempt. Care should be taken not to force the needle into the implant or to use a twisting motion to enter the implant; undue force can lead to device dislocation or septum dislodgement. If the needle is bent, another refill exchange syringe and needle needs to be prepared.

Once the needle is seated completely in the implant, carefully press on the syringe plunger in order to complete the refill exchange. A cotton swab is used for counter pressure as the refill needle is withdrawn. Careful ophthalmoscopy should be performed after the refill to affirm that no septum dislodgement or device dislocation has occurred.

ARCHWAY TRIAL

Background

The pivotal Phase 3 ARCHWAY trial enrolled patients who had been diagnosed with nAMD within 9 months of screening and had been responsive to at least three anti-VEGF therapy injections within 6 months of screening.^11,12 Patients were randomly assigned to treatment with the PDS 100 mg/mL with fixed every 24-week refill-exchange intervals (Q24W), or intravitreal ranibizumab 0.5-mg injections Q4W (monthly ranibizumab) on a 3:2 basis.^11,12 The primary endpoint was defined as a change in the BCVA letter score from baseline, averaged from weeks 36 and 40. Noninferiority and equivalence margins were defined as −4.5 and ±4.5 letters.^11,12 Supplemental intravitreal ranibizumab could be administered at the two study visits preceding each refill-exchange procedure to patients who met protocol-defined criteria based on nAMD disease activity.¹²

At study entry, patients in both the PDS Q24W and monthly ranibizumab had good vision, measuring 74.4 ± 10.5 and 75.5 ± 10.3 letters, respectively.¹¹ Most patients gained vision from the time of diagnosis of nAMD to study entry; a post hoc analysis revealed that patients received a mean of 4.9 ± 1.3 anti-VEGF injections after nAMD diagnosis before entering the study and that patients gained an average of 11.3 letters before receiving their first ARCHWAY study treatment.¹¹ Since most of the visual acuity benefits of anti-VEGF therapy had already been obtained before study enrollment, visual stability and maintenance throughout the duration of ARCHWAY was the expected visual outcome for both groups.

Results

After receiving the PDS implant, there was an expected, postoperative drop in visual acuity,^11,12 which recovered quickly in the PDS group and remained stable through week 96 (Figure). The difference in adjusted weeks 36 and 40 BCVA means between the PDS Q24W and monthly ranibizumab arms was -0.3 letters.^11,12 PDS was therefore both noninferior and equivalent compared with intravitreal ranibizumab. In addition, both groups maintained similar control of retinal center point thickness at baseline through week 96.

An overwhelming majority of PDS-treated patients (about 95%%) did not require supplemental therapy before each 6-month refill procedure.

Ocular adverse events (AEs) of special interest

AEs of particular interest were quantified after an average of 96 weeks of follow-up.¹² The PDS ocular safety profile was generally consistent with the primary analysis after accumulating an average of 38 weeks of additional follow-up. Cataract was more commonly reported in the PDS arm, with an overall incidence of 8.9% compared with 6.0% in the intravitreal ranibizumab group.¹² These cataracts were usually reported as progression of existing cataracts; no traumatic cataract events were reported. The rates of conjunctival AEs were consistent with the primary analysis results. There was a 6.9% incidence of conjunctival bleb (thickening of the conjunctiva over the implant) or conjunctival filtering bleb leak, 4.0% incidence of conjunctival erosion and 2.4% incidence of conjunctival retraction in the PDS group. No conjunctival AEs were reported in the intravitreal ranibizumab group.¹²

The incidence of endophthalmitis was 0.6% in the intravitreal ranibizumab group.¹² In the PDS group, the endophthalmitis incidence was 1.6% (n=4). Three of these cases occurred before week 40; one was late onset after week 40 in a patient who had a repeat endophthalmitis event. This patient was later found to be HLA-B27-positive with an underlying autoimmune condition and had experienced intraocular inflammation episodes in the fellow eye before study enrollment. The patient discontinued study treatment per the investigator’s discretion. Both endophthalmitis events in this patient were culture-negative.¹² Three of the four cases of endophthalmitis were associated with conjunctival retraction; special attention to conjunctival closure during the surgical procedure, as well as early detection and treatment of conjunctival complications may help decrease the risk of endophthalmitis.

The rate of retinal detachment (rhegmatogenous, n=2; 0.8%) was consistent with the primary analysis, with no new events reported after week 40.¹² No retinal detachments were observed in the intravitreal ranibizumab group. Two cases of vitreous hemorrhage occurred after week 40 in the PDS group, for an overall incidence of 6.0% (n=15). Two vitreous hemorrhage cases also occurred in the intravitreal ranibizumab group after week 40, for an overall incidence of 3.6%.¹²

Implant dislocation, occurring in four PDS patients through week 96,¹² were associated with refill-exchange procedures. Upon review of the initial surgical implantation videos, it appeared that these dislocations occurred in patients who had a longer than 3.7-mm initial implant incision. The original surgical protocol allowed for an incision length up to 3.7 mm; this has since been modified to restrict final scleral incision length to 3.5 mm.⁵

Septum dislodgement occurred in three (1.2%) PDS patients in ARCHWAY. This was associated with refill-exchange procedures and likely linked to a twisting motion during the refill-exchange procedure. This was generally not associated with any change in patient vision. Following septum dislodgement, further refill-exchange procedures cannot be performed, and the device must be replaced or maintenance intravitreal ranibizumab must be administered.

PDS IN DME AND DR

PAVILION Trial for DR

PDS is actively being investigated for the treatment of patients with DME and DR. There are two ongoing Phase 3 trials that are examining the safety, efficacy and pharmacokinetics of the PDS in patients with DME and DR.

The PAVILION trial enrolled 160 patients with moderately severe to severe nonproliferative DR without center involving DME (CI-DME). Patients were randomly assigned to treatment with the PDS 100 mg/mL with fixed refill-exchange interval Q36W (n=100) or to clinical observation (n=60).^7,13 Patients received two intravitreal ranibizumab injections before the insertion of the PDS implant.^7,13 The primary endpoint was the percentage of patients with a ≥2-step improvement from baseline based on the Early Treatment Diabetic Retinopathy Study/Diabetic Retinopathy Severity Scale at week 52.^7,13,14 Secondary outcomes include anatomic, safety, VA, and pharmacokinetics assessments. Patients in the observation arm can cross over to the PDS group at week 64 as part of a PDS extension phase.^8,9 Initial results are anticipated to be announced in 2023.²⁸

PAGODA Trial for DME

The PAGODA trial enrolled 545 patients with CI-DME who were randomly assigned to treatment with the PDS 100 mg/mL after fixed 24-week refill-exchange intervals (n=327) or to monthly intravitreal injections of ranibizumab 0.5 mg (n=218).^7,15 The primary outcome is the change in BCVA from baseline, averaged over weeks 60 and 64. Patients in the intravitreal ranibizumab arm can cross over to PDS treatment at week 64. Study completion is estimated in late 2024.¹⁵

CONCLUSION

The PDS offers a novel strategy for patients with nAMD to maintain the clinical benefits of intravitreal anti-VEGF therapy while reducing treatment and visit burden. The pivotal Phase 3 ARCHWAY trial demonstrated that PDS provides visual outcomes equivalent to those achieved with monthly ranibizumab injections in patients with nAMD, leading to FDA approval for this indication in October 2021. Patient Preference Questionnaire data from the ARCHWAY trial indicated that 93% of PDS-treated patients preferred the PDS over intravitreal injections.¹¹ Ocular AEs during PDS treatment were manageable and well characterized.¹²

Meticulous surgical technique including special attention to conjunctival handling, scleral incision length and choroidal laser application can help mitigate complications. In-office refills require good lighting, patient positioning and precise targeting. Utilizing offered training opportunities and leveraging the expertise of surgical device liaisons will help poise vitreoretinal surgeons for success in both surgical implantation and refill procedures.

Further PDS studies are ongoing. The Phase 3 PAVILION and PAGODA trials are assessing the efficacy, safety and pharmacokinetics of the PDS for DR and DME. The single-arm BELVEDERE trial is enrolling patients with nAMD to examine outcomes after PDS treatment in ranibizumab-naive nAMD patients. Post-marketing Phase 4 studies are in the planning stages as well. OM

REFERENCES

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5. Ranibizumab injection for ocular implant. Package insert. Genentech, Inc; 2021.
6. Eyewire News. FDA Approves Genentech’s Port Delivery System, Susvimo, a First-of-Its-Kind Therapeutic Approach for Wet AMD. https://eyewire.news/news/fda-approves-genentechs-port-delivery-system-susvimo-a-first-of-its-kind-therapeutic-approach-for-wet-amd . October 22, 2021. Accessed November 7, 2021.
7. Chang MA, et al. Port delivery system with ranibizumab (PDS) in diabetic retinopathy (DR) with or without diabetic macular edema (DME). Poster 435-P presented at: American Diabetes Association Virtual Session; June 25-29, 2021.
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10. Campochiaro PA, Marcus DM, Awh CC, et al. The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial. Ophthalmology. 2019;126(8):1141-1154.
11. Holekamp NM, Campochiaro PA, Chang MA, et al. Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2022;129(3):295-307.
12. Mittra R, Brooks L, Wykoff CC, et al. MITTRA. Week 96 data reference: Archway Phase 3 Trial of the Port Delivery System With Ranibizumab (PDS) for Neovascular AMD: End-of-Study Results, presented at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting 2022.
13. A Multicenter, Randomized Study in Participants With Diabetic Retinopathy Without Center-involved Diabetic Macular Edema To Evaluate the Efficacy, Safety, and Pharmacokinetics of Ranibizumab Delivered Via the Port Delivery System Relative to the Comparator Arm (PAVILION). ClinicalTrials.gov . https://clinicaltrials.gov/ct2/show/NCT04503551 . Updated February 17, 2022. Accessed February 17, 2022.
14. Chiang A, Garg SJ, Klufas MA, et al. Ultra-Response to Ranibizumab: Improvement by 4 or More Steps in Diabetic Retinopathy Severity in Diabetic Retinopathy Clinical Research Network Protocol S. Ophthalmol Retina. 2021;5(3):251-260.
15. This Study Will Evaluate the Efficacy, Safety, and Pharmacokinetics of the Port Delivery System With Ranibizumab in Participants With Diabetic Macular Edema Compared With Intravitreal Ranibizumab (Pagoda). ClinicalTrials.gov . https://clinicaltrials.gov/ct2/show/NCT04108156 . Updated January 11, 2022. Accessed February 10, 2022.
16. A Study Of The Response to Treatment After Transition to The Port Delivery System With Ranibizumab [Susvimo (Ranibizumab Injection)] In Patients With Neovascular Age-Related Macular Degeneration Previously Treated With Intravitreal Agents Other Than Ranibizumab (Belvedere). ClinicalTrials.gov . https://clinicaltrials.gov/ct2/show/NCT04853251 . Updated January 28, 2022. Accessed February 6, 2022.

Margaret A. Chang, MD, MS is a senior partner at Retinal Consultants, Sacramento, Calif. Email her at changm@retinalmd.com.

Disclosures: Dr Chang is a consultant for Genentech and Regenxbio and provides research support to Allergan, Iveric, Mylan, NGM, Novartis, Opthea and Regeneron.