Evaluation of Surgical Factors Affecting Vitreous Hemorrhage Following Port Delivery System With Ranibizumab Implant Insertion in a Minipig Model

Bantseev, Vladimir; Schuetz, Chris; Horvath, Joshua D.; Hovaten, Kristof; Erickson, Signe; Bentley, Ellison; Nork, T. Michael; Freeman, William R.; Stewart, Jay M.; Barteselli, Giulio

doi:10.1097/iae.0000000000002614

Cited by 24 publications

(17 citation statements)

References 20 publications

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“…As such, the PDS has gone through some optimization to help mitigate some of these risks, such as improving the implant insertion procedure with laser ablation of the pars plana at the scleral incision site, diminishing the rate of vitreous hemorrhage. 19,28 The ongoing Phase III trials should elucidate the safety profile of the PDS further.…”

Section: Discussionmentioning

confidence: 99%

<p>Therapeutic Potential of the Ranibizumab Port Delivery System in the Treatment of AMD: Evidence to Date</p>

Chen

Kaiser

2020

OPTH

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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.

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Section: Discussionmentioning

confidence: 99%

<p>Therapeutic Potential of the Ranibizumab Port Delivery System in the Treatment of AMD: Evidence to Date</p>

Chen

Kaiser

2020

OPTH

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“…Fibrosis adjacent to the implant was observed in both treated animals and controls ( Figure 2), and thus appeared to be due to instability of the implant, which is not optimized for the structure of the pig eye. 15,21 Furthermore, the implant also required suturing to hold it in place, exacerbating the local response. Overall, the PDS implant and associated procedures, such as refilling, were well tolerated in this species.…”

Section: Discussionmentioning

confidence: 99%

“…Since vitreous hemorrhage resolved without intervention within a month of implantation in the majority of animals, and did not limit assessment of safety endpoints during the toxicology study, we developed a minipig surgical model of vitreous hemorrhage where various surgical techniques were evaluated. 15 Another challenge for a drug/device combination product for retinal diseases is related to biocompatibility testing standards, such as ISO 10993. Because ISO 10993 does not apply to ocular implants, it was utilized as a starting point, along with ISO 11979 and ANSI Z80.7 standards.…”

Section: Discussionmentioning

confidence: 99%

“…The Yucatan minipig was selected in a chronic toxicity/TK study (to enable phase 3 and registration) as the appropriate species to assess the PDS because the eye of a minipig (compared with nonhuman primates) is large enough to assess a functional, full-scale clinical implant. 15 The implants were packaged and sterilized by ethylene oxide, the same method used for the clinical implant. Female Yucatan minipigs (Sinclair Research Center) were used in this study (Table 2).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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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.

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“…A minipig surgical model for vitreous hemorrhage with ranibizumab PDS implant was useful for investigation of the insertion of long-acting, indwelling devices into the vitreous cavity and provided important information that may be relevant to similar surgical approaches in different settings. 34 As discussed further in the section on pathology reports, intravitreal injection of some saline solutions in minipigs can cause retinal and other ocular changes that can be difficult to discern from test article-related findings. 35 Minipigs have not been used for intracameral toxicity studies to the author's knowledge, and they have a smaller anterior chamber angle opening distance and angle recess area, which are disadvantages to the more similar angle size in dogs and humans.…”

Section: Minipig Species Selection Considerationsmentioning

confidence: 99%

Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant’s Perspective

Short¹

2020

Toxicol Pathol

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Ocular toxicity studies are the bedrock of nonclinical ocular drug and drug–device development, and there has been an evolution in experience, technologies, and challenges to address that ensures safe clinical trials and marketing authorization. The expectations of a well-designed ocular toxicity study and the generation of a coherent, integrative ocular toxicology report and subreports are high, and this article provides a pathology/toxicology consultant’s perspective on achieving that goal. The first objective is to cover selected aspects of study designs for ocular toxicity studies including considerations for contract research organization selection, minipig species selection, unilateral versus bilateral dosing, and in-life parameters based on fit-for-purpose study objectives. The main objective is a focus on a high-quality ocular pathology report that includes ocular histology procedures to meet regulatory expectations and a report narrative and tables that correlate microscopic findings with key ophthalmic findings and presents a clear interpretation of test article-, vehicle-, and procedure-related ocular and extraocular findings with identification of adversity and a pathology peer review. The last objective covers considerations for a high-quality ophthalmology report, which in concert with a high-quality pathology report, will pave the way for a best quality toxicology report for an ocular toxicity study.

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Evaluation of Surgical Factors Affecting Vitreous Hemorrhage Following Port Delivery System With Ranibizumab Implant Insertion in a Minipig Model

Cited by 24 publications

References 20 publications

<p>Therapeutic Potential of the Ranibizumab Port Delivery System in the Treatment of AMD: Evidence to Date</p>

<p>Therapeutic Potential of the Ranibizumab Port Delivery System in the Treatment of AMD: Evidence to Date</p>

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

Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant’s Perspective

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