Stability of ranibizumab during continuous delivery from the Port Delivery Platform.

The Port Delivery System with ranibizumab (PDS) is an innovative intraocular drug delivery system that has the potential to reduce treatment burden in patients with retinovascular diseases. The Port Delivery Platform (PD-P) implant is a permanent, indwelling device that can be refilled in situ through a self-sealing septum and is designed to continuously deliver ranibizumab by passive diffusion through a porous titanium release control element. We present results for the studies carried out to characterize the stability of ranibizumab for use with the PD-P. Simulated administration, in vitro release studies, and modeling studies were performed to evaluate the compatibility of ranibizumab with the PD-P administration components, and degradation and photostability in the implant. Simulated administration studies demonstrated that ranibizumab was highly compatible with the PD-P administration components (initial fill and refill needles) and commercially available administration components (syringe, transfer needle, syringe closure). Subsequent simulated in vitro release studies examining continuous delivery for up to 12 months in phosphate buffered saline, a surrogate for human vitreous, showed that the primary degradation products of ranibizumab were acidic variants. The presence of these variants increased over time and potency remained high. The stability attributes of ranibizumab were consistent across multiple implant refill-exchanges. Despite some degradation within the implant, the absolute mass of variants released daily from the implant was low due to the continuous release mechanism of the implant. Simulated light exposure within the implant resulted in small increases in the relative amount of ranibizumab degradants compared with those seen over 6 months.

The Port Delivery System with ranibizumab: a new paradigm for long-acting retinal drug delivery.

The Port Delivery System with ranibizumab (PDS) is an innovative intraocular drug delivery system designed for the continuous delivery of ranibizumab into the vitreous for 6 months and beyond. The PDS includes an ocular implant, a customized formulation of ranibizumab, and four dedicated ancillary devices for initial fill, surgical implantation, refill-exchange, and explantation, if clinically indicated. Ranibizumab is an ideal candidate for the PDS on account of its unique physicochemical stability and high solubility. Controlled release is achieved via passive diffusion through the porous release control element, which is tuned to specific drug characteristics to accomplish a therapeutic level of ranibizumab in the vitreous. To characterize drug release from the implant, release rate was measured in vitro with starting concentrations of ranibizumab 10, 40, and 100 mg/mL, with release of ranibizumab 40 and 100 mg/mL found to remain quantifiable after 6 months. Using a starting concentration of 100 mg/mL, active release rate at approximately 6 months was consistent after the initial fill and first, second, and third refills, demonstrating reproducibility between implants and between multiple refill-exchanges of the same implant. A refill-exchange performed with a single 100-µL stroke using the refill needle was shown to replace over 95% of the implant contents with fresh drug. In vitro data support the use of the PDS with fixed refill-exchange intervals of at least 6 months in clinical trials.

In-vitro characterization of ranibizumab release from the Port Delivery System.

The Port Delivery System with ranibizumab (PDS) consists of an implant that is a permanent, indwelling drug delivery device that can be refilled through a self-sealing septum and is designed to continuously release a customized formulation of ranibizumab into the vitreous by passive diffusion through a porous titanium release control element. Target release rates of ranibizumab via the implant used in studies of the PDS in patients with neovascular age-related macular degeneration were selected based on clinical and pharmacokinetic (PK) data from previously conducted intravitreal ranibizumab injection studies. In-vitro testing was performed to verify release rates with a range of ranibizumab concentrations before the phase II Ladder (NCT02510794) and phase III Archway (NCT03677934) trials of the PDS. Implants were filled with ranibizumab and were regularly transferred to new buffer-containing tubes to represent ocular ranibizumab clearance and release kinetics. Ranibizumab concentrations were measured and release rates calculated. Release rate data were fit to an exponential model and compared with expected release kinetics of diffusion. Release profiles of the implant releasing ranibizumab at concentrations of 10 mg/mL, 40 mg/mL, and 100 mg/mL were determined in the pre-phase II in-vitro studies. At day 3.5, mean (SD) ranibizumab release rates were 1.75 (0.07), 6.42 (0.35), and 16.69 (0.67) µg/d for PDS 10 mg/mL, 40 mg/mL, and 100 mg/mL, respectively. At month 6, mean (SD) release rates were 1.68 (0.05) and 4.16 (0.05) µg/d for PDS 40 mg/mL and 100 mg/mL, respectively. Measured release rates were within 90% of theoretical release rates during the course of drug release. PDS 100 mg/mL released 73% (SD, 1.92) of drug by month 6. In the pre-phase III in-vitro studies, mean (SD) release rates with PDS 100 mg/mL were 17.97 (0.90), 4.44 (0.11), and 2.45 (0.08) µg/d at 3.5 days, 6 months, and 9 months, respectively. Cumulative release (SD) was 73% (1.92) by month 6 and 87% (1.88) by month 9. The sustained, continuous, and reproducible release from the PDS observed in the in-vitro studies was also observed in Ladder and Archway. In conclusion, in-vitro studies were a powerful tool for characterizing and verifying ranibizumab release from the PDS implant and supported clinical evaluation of the PDS. PDS 100 mg/mL, which was associated with the longest therapeutic-level delivery of ranibizumab among the concentrations tested, was selected for evaluation in the pivotal phase III Archway trial.

Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. PARTICIPANTS: Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). MAIN OUTCOME MEASURES: Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). RESULTS: Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. CONCLUSIONS: Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.

A custom virtual reality training solution for ophthalmologic surgical clinical trials.

We present a summary of the development and clinical use of two custom designed high-fidelity virtual-reality simulator training platforms. This simulator development program began in 2016 to support the phase III clinical trial Archway (ClinicalTrials.gov identifier, NCT03677934) intended to evaluate the Port Delivery System (PDS) developed by Genentech Inc. and has also been used to support additional clinical trials. The two simulators address two specific ophthalmic surgical procedures required for the successful use of PDS and provide state-of-the-art physical simulation models and graphics. The simulators incorporate customized active haptic feedback input devices that approximate different hand pieces including a custom hand piece specifically designed for PDS implantation. We further describe the specific challenges of the procedure and the development of corresponding training strategies realized within the simulation platform.

Nonclinical Toxicology and Biocompatibility Program Supporting Clinical Development and Registration of the Port Delivery System With Ranibizumab for Neovascular Age-Related Macular Degeneration.

The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed to provide continuous intravitreal release of ranibizumab for extended durations. The PDS consists of a permanent, surgically placed, refillable intraocular implant; a customized formulation of ranibizumab; and ancillary devices to support surgery and refill procedures. A toxicology program was conducted to evaluate the ocular toxicology and biocompatibility of the PDS to support its clinical development program and product registrational activities. PDS safety studies included a 6-month chronic toxicology evaluation in minipigs as well as evaluation of nonfunctional surrogate implants (comprised of the same implant materials but without ranibizumab) in rabbits. Biocompatibility of the implant and ancillary devices was evaluated in both in vitro and in vivo studies. Implants and extracts from implants and ancillary devices were nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. Ocular findings were comparable between implanted and sham-operated eyes, and no systemic toxicity was observed. The results of this nonclinical toxicology program demonstrated that the PDS was biocompatible and that intravitreal delivery of ranibizumab via the PDS did not introduce any new toxicology-related safety concerns relative to intravitreal injections, supporting ongoing PDS clinical development and product registrational evaluation.

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.

Suture fixation of migrated septal occluder device to prevent further migration: a simple surgical technique.

As the use of percutaneous intervention is increasing for the closure of the atrial septal defect, the procedure related complications are also on rise, migration of the device being most common. The migrated devices with failed percutaneous retrieval must be removed surgically under cardiopulmonary bypass. During establishment of cardiopulmonary bypass, the handling of heart may cause further migration of the device into other chambers of heart which leads to difficulty in finding and retrieval of the device. The authors propose a simple and unique technique to prevent further migration of the septal occluder device.

Evaluation of acrylate-based block copolymers prepared by atom transfer radical polymerization as matrices for paclitaxel delivery from coronary stents.

Acrylate-based block copolymers, synthesized by atom transfer radical polymerization (ATRP) processes, were evaluated as drug delivery matrices for the controlled release of paclitaxel from coronary stents. The polymers were multiblock copolymers consisting of poly(butyl acrylate) or poly(lauryl acrylate) soft blocks and hard blocks composed of poly(methyl methacrylate), poly(isobornyl acrylate), or poly(styrene) homo- or copolymers. Depending on the ratio of hard to soft blocks in the copolymers, coating formulations were produced that possessed variable elastomeric properties, resulting in stent coatings that maintained their integrity when assessed by scanning electron microscopy (SEM) imaging of overexpanded stents. In vitro paclitaxel release kinetics from coronary stents coated with these copolymers typically showed an early burst followed by sustained release behavior, which permitted the elution of the majority of the paclitaxel over a 10-day time period. It was determined that neither the nature of the polyacrylate (n-butyl or lauryl) nor that of the hard block appeared to affect the release kinetics of paclitaxel at a loading of 25% drug by weight, whereas some effects were observed at lower drug loading levels. Differential scanning calorimetry (DSC) analysis indicated that the paclitaxel was at least partially miscible with the poly(n-butyl acrylate) phase of those block copolymers. The copolymers were also evaluated for sterilization stability by exposing both the copolymer alone and copolymer/paclitaxel coated stents to e-beam radiation at doses of 1-3 times the nominal dose used for medical device sterilization (25 kGy). It was found that the copolymers containing blocks bearing quaternary carbons within the polymer backbone were less stable to the radiation and showed a decrease in molecular weight as determined by gel-permeation chromatography. Conversely, those without quaternary carbons showed no significant change in molecular weight when exposed to 3 times the standard radiation dose. There was no significant change in drug release profile from any of the acrylate-based copolymers after exposure to 75 kGy of e-beam radiation, and this was attributed to the inherent radiation stability of the poly(n-butyl acrylate) center block.

NMR characterization of paclitaxel/poly (styrene-isobutylene-styrene) formulations.

TAXUStrade mark is a coronary drug-eluting stent system utilizing a formulation consisting of cellular-target drug paclitaxel and poly (styrene-isobutylene-styrene) (SIBS). The present study investigates the interaction and interfacial dynamics of paclitaxel incorporated in a nano-polymeric matrix system. Solution and solid-state CP/MAS NMR experiments were designed to characterize the microstructure of heterogeneous drug-polymer mixtures in terms of its composition, molecular mobility, molecular order, paclitaxel-SIBS molecular interactions, and molecular mobility of the drug in the polymer matrix. The NMR spectra demonstrated unchanged chemical shifts between the neat and incorporated paclitaxel, and suggested that the level of the interactions between paclitaxel and SIBS is limited to non-bonding interactions or physical interactions between paclitaxel and SIBS when mixed in solution under NMR detection. Carbon spin-lattice relaxation time and proton spin-lattice relaxation time in the rotating frame offer further confirmation that the mobility of paclitaxel is increased in the paclitaxel-SIBS mixture. The results also indicate that a change occurs from crystalline packing to amorphous packing in paclitaxel due to its intermolecular interaction with SIBS. Our studies were used in understanding the detailed structure, morphology, and molecular motion of paclitaxel in the paclitaxel-SIBS system and to probe chemical and physical heterogeneity down to the nanometer scale.

Controlled delivery of paclitaxel from stent coatings using poly(hydroxystyrene-b-isobutylene-b-hydroxystyrene) and its acetylated derivative.

A poly(styrene-b-isobutylene-b-styrene) (SIBS) triblock polymer is employed as the polymer drug carrier for the TAXUS Express2 Paclitaxel-Eluting Coronary Stent system (Boston Scientific Corp.). It has been shown that the release of paclitaxel (PTx) from SIBS can be modulated by modification of either drug-loading ratio or altering the triblock morphology by blending. In the present work, results toward achieving release modulation of PTx by chemical modification of the styrenic portion (using hydroxystyrene or its acetylated version) of the SIBS polymer system are reported. The synthesis of the precursor poly[(p-tert-butyldimethylsilyloxystyrene)]-b-isobutylene-b-[(p-tert-butyldimethylsilyloxystyrene] triblock copolymers was accomplished by living sequential block copolymerization of isobutylene (IB) and p-(tert-butyldimethylsiloxy)styrene (TBDMS) utilizing the capping-tuning technique in a one-pot procedure in methylcyclohexane/CH3Cl at -80 degrees C. This procedure involved the living cationic polymerization of IB with the 5-tert-butyl-1,3-bis(1-chloro-1-methylethyl)benzene/TiCl4 initiating system and capping of living difunctional polyisobutylene (PIB) chain ends with 1,1-ditolylethylene (DTE) followed by addition of titanium(IV) isopropoxide (Ti(OIp)4) to lower the Lewis acidity before the introduction of TBDMS. Deprotection of the product with tetrabutylammonium fluoride yielded poly(hydroxystyrene-b-isobutylene-b-hydroxystyrene), which was quantitatively acetylated to obtain the acetylated derivative. The hydroxystyrene and acetoxystyrene triblock copolymers have acceptable mechanical properties for use as drug delivery coatings for coronary stent applications. It was concluded that the hydrophilic nature of the endblocks and polarity effects on the drug/polymer miscibility lead to enhanced release of PTx from these polymers. The drug-polymer miscibility was confirmed by differential scanning calorimetry and atomic force microscopy evaluations.

Styrenic block copolymers for biomaterial and drug delivery applications.

The use of styrenic block copolymers has undergone a renaissance as a biomaterial and drug delivery matrix. The early promise posed by the physical and biological properties of these block copolymers for implantable medical devices was not met. However, there has been an increased understanding of the role of microphase separation on the mediation of the biological response. Poly (styrene-b-isobutylene-b-styrene) (SIBS) block copolymer has critical enabling properties related to processing, vascular compatibility and bio-stability that has resulted in its use as the matrix for paclitaxel delivery from Boston Scientific's TAXUS coronary stent. These enabling properties will allow the continuing development of medical devices based on SIBS that meet demanding physical and biological requirements.

Physical characterization of controlled release of paclitaxel from the TAXUS Express2 drug-eluting stent.

The polymer carrier technology in the TAXUS drug-eluting stent consists of a thermoplastic elastomer poly(styrene-b-isobutylene-b-styrene) (SIBS) with microphase-separated morphology resulting in optimal properties for a drug-delivery stent coating. Comprehensive physical characterization of the stent coatings and cast film formulations showed that paclitaxel (PTx) exists primarily as discrete nanoparticles embedded in the SIBS matrix. Thermal and chemical analysis did not show any evidence of solubility of PTx in SIBS or of any molecular miscibility between PTx and SIBS. Atomic force microscope data images revealed for the first time three-dimensional stent coating surfaces at high spatial resolutions in air and in situ under phosphate-buffered saline as drug was released. PTx release involves the initial dissolution of drug particles from the PTx/SIBS coating surface. Morphological examination of the stent coatings in vitro supported an early burst release in most formulations because of surface PTx followed by a sustained slower release of PTx from the bulk coating. The in vitro PTx release kinetics were dependent on the formulation and correlated to the drug-to-polymer ratio. Atomic force microscopy analysis confirmed this correlation and further supported the concept of a matrix-based drug-release coating.