Port Delivery System Research Articles

Long-Term Stability of Anti-Vascular Endothelial Growth Factor (a-VEGF) Biologics Under Physiologically Relevant Conditions and Its Impact on the Development of Long-Acting Delivery Systems.

The port delivery system with ranibizumab (PDS) is an investigational long-acting drug delivery system for the continuous release of ranibizumab, an anti-VEGF biologic, in the vitreous humor. The efficacy of the PDS implant relies on the maintenance of long-term drug stability under physiological conditions. Herein, the long-term stability of three anti-VEGF biologics - ranibizumab, bevacizumab and aflibercept - was investigated in phosphate buffered saline (PBS) at 37°C for several months. Comparison of stability profiles shows that bevacizumab and aflibercept are increasingly prone to aggregation whereas ranibizumab undergoes minimal aggregation. Ranibizumab also shows the smallest loss in antigen binding capacity after long-term incubation in PBS. Even though the aggregated forms of bevacizumab and aflibercept bind to VEGF, the consequences of aggregation on immunogenicity, implant function and efficacy are unknown. These results highlight the importance of maintaining long-term drug stability under physiologically relevant conditions which is necessary for achieving efficacy with an invivo continuous drug delivery device such as the PDS implant.

New Anti-VEGF Drugs in Ophthalmology.

This review focuses on 5 new anti-VEGF drugs in the advanced stage of clinical development (i.e., phase 3): conbercept, brolucizumab, port delivery system with ranibizumab, abicipar pegol and faricimab. Results of clinical trials and the advantages of each drug compared to the available molecules are discussed in detail.

Gene, Cell and Antibody-Based Therapies for the Treatment of Age-Related Macular Degeneration.

Here we discuss antibody, cell and gene-based therapies that are currently available and under investigation for both wet and dry age-related macular degeneration (AMD). We initially discuss ocular anatomy, AMD modelling as well as the underlying pathophysiology of AMD. The antibody-based trials which have revolutionised the management of wet AMD are reviewed. The latest concepts in antibody therapy for wet AMD such as the port delivery systems, bispecific antibodies, designed ankyrin repeat protein (DARPINs) and brolucizumab are explored. Furthermore, the antibody-based trials targeting the complement pathway to reduce progression of geographic atrophy (GA) in dry AMD are discussed. Stem cell therapy and gene therapy are novel treatment modalities with no established clinical use in wet or dry AMD. Here, we discuss their efficacy so far in clinical trials. Their benefits and risk in the treatment of both wet and dry AMD are evaluated.

An overview of the pathophysiology and the past, current, and future treatments of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in New Zealand and other developed countries. Neovascular AMD has a rapid onset and can lead to an overall loss of independence. Patients often present with an absolute central scotoma and distortion. The pathophysiology of neovascular AMD is thought to be associated with polymorphisms and mutations in genes which are involved with the progression of the complement cascade. Vascular endothelial growth factor (VEGF) may contribute to the progression of AMD via excessive angiogenesis and permeability of vessels associated with the retina. Current treatments for neovascular AMD act to reduce pathological angiogenesis via multiple mechanisms. Bevacizumab and ranibizumab bind to VEGF receptor 2 (VEGFR2), suppressing the actions of VEGF-A. Similar drugs, such as aflibercept, bind to placental growth factor (PIGF) in addition to VEGFR2, triggering similar effects. Endeavours to improve current treatments such as the safer use of brolucizumab and the use of the port delivery system for ranibizumab are being researched to maximise efficiency of therapies, to meet increasing demand. There are many direct and indirect costs of AMD on patients and hospitals. With an ageing population who suffer from more comorbidities, AMD cases are expected to rise; we must therefore endeavour to improve existing treatments, and future techniques for management should not be discarded without serious consideration.

Virtual Reality Becomes a Reality for Ophthalmologic Surgical Clinical Trials.

The Port Delivery System with ranibizumab (PDS) is an innovative, investigational drug delivery system designed for continuous delivery of ranibizumab into the vitreous to maintain therapeutic drug concentrations for extended durations. The phase 2 Ladder trial (NCT02510794) tested the efficacy of three customized formulations of ranibizumab in patients with neovascular age-related macular degeneration, and the phase 3 Archway trial (NCT03677934) will further assess the safety and efficacy of PDS 100 mg/mL with fixed 24-week refills. The insertion of the PDS implant into the vitreous cavity and subsequent refill-exchange of the drug require procedural skills that are not directly transferable from everyday experience for most eye surgeons today. Preoperative practice for the PDS implant insertion and refill-exchange procedures is therefore critical for achieving optimal surgical outcomes. Virtual reality (VR) as a training tool has long been used by the aeronautic industry and more recently adapted for physician training in medicine and surgery, with encouraging results. Besides the primary use of traditional training tools, physicians participating in Archway have an option to practice in computer-simulated environments provided by VR simulators before performing their first PDS implant insertion and refill-exchange procedures on patients. This Perspective article describes the unique advantages and technologic challenges that practice on VR simulators has to offer, and the experience of Archway physicians with VR technology as a first in any ophthalmic clinical trial.

Therapeutic Potential of the Ranibizumab Port Delivery System in the Treatment of AMD: Evidence to Date.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in older adults worldwide. The advent of intravitreal neutralization of vascular endothelial growth factor (VEGF) has revolutionized the management of patients with neovascular AMD, but current anti-VEGF therapies carry a high threshold of patient burden. The ranibizumab port delivery system (PDS) is an implanted, refillable reservoir that continuously supplies the anti-VEGF medication ranibizumab directly into the vitreous, eliminating the need for frequent intravitreal injections. It has most recently been evaluated in the Phase II LADDER trial demonstrating the efficacy and safety of the PDS, with Phase III trials currently underway. This review presents both the promise and drawbacks of the PDS in the treatment of AMD from the current literature.

Wet age-related macular degeneration: treatment advances to reduce the injection burden.

The burden of age-related macular degeneration (AMD), a leading cause of vision loss in the elderly population, is poised to increase dramatically as the baby boomer generation ages. Fortunately, the prognosis of neovascular AMD has improved dramatically since anti-vascular endothelial growth factor (VEGF) agents reached the market 15 years ago. In large-scale clinical trials, anti-VEGF utilization maintained visual acuity in more than 90% of patients. However, providing anti-VEGF treatment requires the specialized expertise of retina specialists and is labor intensive and costly. Further, results in clinical practice do not always measure up to those obtained in rigorous phase 3 trials. Undertreatment and the burden on patients and caregivers from frequent anti-VEGF injections contribute to suboptimal visual acuity results in the real world. As a consequence, retinal specialists are focused on finding effective strategies to extend the dosing interval. These include individualized optical coherence tomography-guided dosing regimens, longer acting new agents with similar or new mechanisms of action, and sustained release delivery devices. With the recent approval of brolucizumab, the neovascular AMD armamentarium has expanded to 4 anti-VEGF agents, and more are in development. Understanding the treatment landscape is a key issue in managed care due to the substantial cost of anti-VEGF medications. The goal of this article is to provide managed care clinicians with an up-to-date assessment of currently available agents, followed by a preview of some investigational agents that could alter the future treatment landscape. These agents include abicipar pegol, faricimab, the ranibizumab port delivery system, an intravitreal bevacizumab formulation, and anti-VEGF biosimilars.

This Study Will Evaluate the Efficacy, Safety, and Pharmacokinetics of the Port Delivery System With Ranibizumab (PDS) in Participants With Diabetic Macular Edema (DME) Compared With Intravitreal Ranibizumab

This Study Will Evaluate the Efficacy, Safety, and Pharmacokinetics of the Port Delivery System With Ranibizumab (PDS) in Participants With Diabetic Macular Edema (DME) Compared With Intravitreal Ranibizumab

Surgical Innovations in the Treatment of Diabetic Macular Edema and Diabetic Retinopathy.

Diabetic macular edema (DME) and complications of proliferative diabetic retinopathy (PDR) are the primary causes of vision loss in patients with diabetic retinopathy. As the incidence of diabetes increases worldwide, new, cost-effective treatments for DME and PDR will become paramount. Currently, anti-vascular endothelial growth factor (anti-VEGF) medications are considered first-line treatment. However, multiple visits for injections and the economic and time burden they entail make this treatment modality less than ideal. Early vitrectomy as well as depot delivery systems for medications could potentially reduce the treatment burden of patients with diabetes, prevent visual loss, and provide long-term stabilization of retinopathy in patients with diabetes. Newer port delivery systems for anti-VEGF medications could oneday make this treatment modality better suited for patients across the globe. Real-world data shows poor compliance with treatment among patients with diabetes. Recent publications show catastrophic results when anti-VEGF treatments are stopped abruptly. The port delivery system for ranibizumab shows maintenance of adequate anti-VEGF levels in the vitreous cavity for many months. Early vitrectomy can provide cost-effective long-term stabilization in eyes with diabetic retinopathy. Microincisional vitrectomy as a treatment for DME and PDR remains controversial and larger trials are needed to definitively prove its superiority over other modalities; however, small-scale data point towards its usefulness in specific populations. Newer port delivery systems of anti-VEGF show promise in decreasing the number of office visits in patients with diabetic retinopathy.

EVALUATION OF SURGICAL FACTORS AFFECTING VITREOUS HEMORRHAGE FOLLOWING PORT DELIVERY SYSTEM WITH RANIBIZUMAB IMPLANT INSERTION IN A MINIPIG MODEL.

To develop an animal model of vitreous hemorrhage (VH) to explore the impact of surgical parameters on VH associated with insertion of the Port Delivery System with ranibizumab (PDS) implant. Ninety eyes from 45 treatment-naive male Yucatan minipigs received PDS implant insertion or a sham procedure. The effect of prophylactic pars plana hemostasis, scleral incision length, scleral cauterization, surgical blade type/size, and viscoelastic usage on postsurgical VH was investigated. Postsurgical VH was detected in 60.0% (54/90) of implanted eyes. A systematic effect on VH was only detected for pars plana hemostasis before the pars plana incision. The percentage of eyes with VH was 96.6% (28/29) among eyes that did not receive prophylactic pars plana hemostasis and 42.4% (24/58) among eyes that did. There was no VH in eyes that received laser ablation of the pars plana using overlapping 1,000-ms spots; pars plana cautery or diathermy was less effective. The majority of all VH cases (83.3% [45/54]) were of mild to moderate severity (involving ≤25% of the fundus). In this minipig surgical model of VH, scleral dissection followed by pars plana laser ablation before pars plana incision most effectively mitigated VH secondary to PDS implant insertion.

Ranibizumab port delivery system (RPDS): realising long awaited dream of prolonged VEGF suppression.

Ranibizumab port delivery system (RPDS): realising long awaited dream of prolonged VEGF suppression.

The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial

To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) treatment. Phase 2, multicenter, randomized, active treatment-controlled clinical trial. Patients diagnosed with nAMD within 9 months who had received 2 or more prior anti-vascular endothelial growth factor intravitreal injections and were responsive to treatment. Patients were randomized 3:3:3:2 to receive the PDS filled with ranibizumab 10 mg/ml, 40 mg/ml, 100 mg/ml, or monthly intravitreal ranibizumab 0.5-mg injections. Time to first implant refill assessed when the last enrolled patient completed the month 9 visit (primary efficacy end point), improvement in best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. The primary analysis population was 220 patients, with 58, 62, 59, and 41 patients in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. Median time to first implant refill was 8.7, 13.0, and 15.0 months in the PDS 10-mg/ml, PDS 40-mg/ml, and PDS 100-mg/ml arms, respectively. At month 9, the adjusted mean BCVA change from baseline was ‒3.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒0.5 ETDRS letters,+5.0 ETDRS letters, and+3.9 ETDRS letters in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. At month 9, the adjusted mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms. The optimized PDS implant insertion and refill procedures were generally well tolerated. After surgical procedure optimization, postoperative vitreous hemorrhage rate was 4.5% (7/157; 1 event classified as serious). There was no evidence of implant clogging. In the phase 2 Ladder trial, the PDS was generally well tolerated and demonstrated a dose response across multiple end points in patients with nAMD. The PDS 100-mg/ml arm showed visual and anatomic outcomes comparable with monthly intravitreal ranibizumab 0.5-mg injections but with a reduced total number of ranibizumab treatments. The PDS has the potential to reduce treatment burden in nAMD while maintaining vision.

Innovation in Neovascular Age-Related Macular Degeneration: Consideration of Brolucizumab, Abicipar, and the Port Delivery System.

Innovation in Neovascular Age-Related Macular Degeneration: Consideration of Brolucizumab, Abicipar, and the Port Delivery System.

Outcomes associated with different intraperitoneal chemotherapy delivery systems in advanced ovarian carcinoma: A single institution's experience

Background Despite increasing use of intraperitoneal chemotherapy the optimal delivery strategy and regimen remain undetermined. Catheter-related complications have been reported in 3–34% of cases across a number of platforms and port styles, but few data compare different catheters directly. We sought to evaluate the complication rate of two separate intraperitoneal chemotherapy port delivery systems used within a single practice. Methods We reviewed the medical records of all patients who underwent port placement in our practice (two surgical centers) from January, 2006 through October, 2008. Data extracted included: demographics, medical co-morbidities, port type, timing of placement, intraoperative procedures, reasons for discontinuation of IP chemotherapy, and number of completed cycles. Results We identified 85 patients who had intraperitoneal ports placed. Four patients were excluded from this analysis: 2 declined chemotherapy and 2 were treated at other institutions and follow-up data was insufficient. Fifty-two (64%) of the 81 patients analyzed had a fenestrated port placed, and 29 (36%) had single lumen ports. In 67 cases (83%) the port was placed at the time of initial cytoreductive surgery. In 14 patients (17%) it was placed as a secondary event. The groups were well matched for age, stage, BMI, and medical co-morbidities though the group with single lumen catheters had more antecedent surgeries. We observed no significant difference between patients with single lumen or fenestrated ports with regard to: number of intraperitoneal treatments, catheter-related complications, hematologic outcomes, and rates of discontinuation. Conclusions A low rate of catheter-related complications is observed with both systems. The majority of discontinuations were due to hematologic complications and did not appear to be intrinsic to catheter choice.