Medidur Insert Technology

PRITHVI MRUTHYUNJAYA, MD, GLENN J. JAFFE, MD

Medidur FA (Alimera Sciences, Inc., Alpharetta, GA/pSivida Inc., Watertown, MA) is a new-generation fluocinolone acetonide (FA) sustained-release intravitreal insert designed for delivery in an office setting. The Medidur device platform is based on the Retisert (Bausch & Lomb, Rochester, NY) FA intravitreal implant, the only Food and Drug Administration (FDA)-approved, ocular sustained-release steroid device in clinical practice, currently labeled to treat noninfectious uveitis.¹ Control Delivery Systems, Inc. (now pSivida, Inc., which has recently signed a worldwide collaborative research and license agreement with Pfizer for their ophthalmic sustained-delivery technology) developed both delivery systems, but the Medidur implant seeks to deliver lower FA doses while eliminating the need for surgical implantation. Medidur is now in phase 3 clinical trials for diabetic macular edema (DME).

CONSTRUCTION AND DELIVERY

Fluocinolone acetonide is a synthetic fluorinated corticosteroid that has low aqueous solubility, making it an excellent choice as a slowly dissolving drug reservoir. With the Retisert device, a 0.5-mg FA drug core is coated with a silicone polyvinyl alcohol (PVA) laminate and has a release opening covered by PVA and attached to a PVA suture tab. The implant is secured to the sclera through a 4-mm pars plana operative incision and is designed to release 0.59 μg of FA per day for approximately 3 years.²

The Medidur insert consists of a 180 μg FA core surrounded by a 3.5-mm polyimide cylinder (Figure). Once cured, PVA end caps are applied, which regulate the drug release rate (2 different release-rate inserts are currently in clinical trials: 0.5 and 0.2 μg/day). Medidur FA is then loaded into a 25-g needle attached to a modified tuberculin syringe and injected through the needle tip with the aid of a specially designed plunger. Alimera is currently developing a more user-friendly injector for commercial use. The insert is predicted to release FA for 1.5 and 3 years with the 0.5 μg/day and 0.2 μg/day devices, respectively.

The Medidur insert is delivered in an office setting with the use of a lid speculum and povidone-iodine preparation of the conjunctiva. A local cotton tip applicator soaked with topical lidocaine is sufficient to anesthetize the inferior quadrant for insertion. The needle guard is removed and the implant is verified in the needle shaft. The conjunctiva is displaced and the 25-g needle is inserted in a beveled manner through the conjunctiva and sclera over the inferior pars plana. The plunger is depressed and the device is released into the inferior vitreous base region. It is not uncommon for the device to lie perpendicular to the needle tip within the eye. The needle is withdrawn and the conjunctiva returned to its normal position over the self-sealing wound. The implant position is confirmed by indirect ophthalmoscopy.

PRECLINICAL STUDIES

Studies have confirmed FA's safety and pharmacokinetic profiles. Efficacy has been studied in animal models of uveitis and proliferative vitreoretinopathy (PVR) and in human trials of uveitis, vein occlusion, and macular edema. These studies were performed in early-generation Retisert-like devices with release rates ranging from 0.6 to3.26 μg/day.^3-7 These data helped to guide development of the smaller Medidur insert that consists of the same drug core.

In vitro studies with the Medidur insert have demonstrated a linear drug release profile over a 27- to 30-day test period. See et al. reported long-term in vitro pharmacokinetic results in rabbit eyes using 0.3 μg/day and 0.5 μg/day devices over 11 and 12 months, respectively. The 0.3 μg/day devices demonstrated more constant and linear release (0.27 +/-0.03 μg/day) than 0.5 μg/day devices, which had higher initial release rates (0.70 +/-0.07 μg/day) in the first 9 months, decreasing to a linear release of 0.30 +/-0.05 μg/day, remaining constant over the next 12 months.⁸

A 12-month safety study was performed to evaluate insertion-related complications, ocular inflammation, and retinal and electrophysiological changes on 45 New Zealand albino rabbits, using both the 0.3 and 0.5 μg/day devices, evaluating insertion-related complications, ocular inflammation, and retinal and electrophysiological changes. By clinical examination, all devices, from both insert groups, were well tolerated at all time points. There was no observable anterior-segment inflammation, neovascularization, fibrin, or vitreous opacity. Crystalline lens opacities were seen in 9 eyes. The insert directly contacted the lens in 3 eyes and there was minimal focal lens opacity in the other 6 eyes. No eyes developed a retinal detachment and PVR was not observed. The inserts did not degrade in any eye and were visualized in all animals sacrificed at the 12-month time point. Electroretinography that compared the inserted to fellow eye B-wave amplitudes, were not altered. This study concluded that the Medidur inserts were safe and well tolerated, up to 1 year, in rabbit eyes.⁸

Srivastava et al. implanted 0.6 μg/day and 1.0 μg/day Medidur inserts in a Mycobacterium tuberculosis rabbit model of endogenous uveitis. Compared to control eyes, the FA�device-implanted eyes were significantly less inflamed in a dose-dependent manner.⁹

For the ongoing phase 3 clinical trials, inserts targeted at 0.5 μg/day and 0/2 μg/day are being studied, where in vitro stability data show a near zero-order release profiles that has been followed out to 18 months so far (personal communication, Alimera Sciences).

CORTICOSTEROID THERAPY IN DME

Macular edema remains the leading cause of vision loss in the 5.3 million adults with diabetic retinopathy (DR) currently in the United States, with an estimated 25 million adults with diabetes predicted to be afflicted with DME by 2025. The "standard of care" treatment for DME remains focal macular laser photocoagulation as outlined by the Early Treatment of Diabetic Retinopathy Study (ETDRS).¹⁰

Corticosteroids are used to treat many retinal conditions, including uveitis, complications of retinal vein occlusion, and age-related macular degeneration. In DME, corticosteroids may be particularly effective, as they are known to decrease VEGF, intercellular adhesion molecule (ICAM)-1, and stromal derived factor. Clinical studies using periocular or intravitreal triamcinolone acetonide (TA; Kenalog, Bristol-Myers Squibb) have shown a positive effect in reducing macular thickness and improving visual acuity (VA).^11-13 Local delivery of corticosteroid places it in close proximity to target tissues while minimizing systemic side effects observed with oral delivery, but repeated injections every 3 to 6 months are typically required to maintain a treatment effect. Sustained-release corticosteroid delivery has potential advantages over periocular or intravitreal injections and provides constant drug levels over the insert lifespan, reducing cycling through peak and trough drug concentrations encountered with each injection.

Figure. The Medidur FA insert, placed next to a US dime to show its size.

FLUOCINOLONE ACETONIDE STUDIED IN DME

For registration of a pharmacologic treatment for DR, the FDA requires a clinically relevant treatment effect (change from baseline of 3 lines of best corrected VA on ETDRS vision charts) after 3 years. The rationale for the Medidur insert in DME trials is based on 2 separate multiyear, randomized, multicenter phase 2b/3 clinical trials with the Retisert FA delivery platform in DME patients.

The first study (Retisert DME Study 002) enrolled 80 adults with DME at least 1 disc area in size involving the central fovea, despite at least 1 prior macular laser in the study eye more than 3 months before entry. Exclusion criteria included a history of uncontrolled intraocular pressure (IOP) while on steroid therapy despite up to 2 IOP-lowering medications. Subjects were randomized to either standard of care (SOC), consisting of macular grid laser or observation, or FA inserts releasing at 0.5 or 2.0 μg/day. The primary endpoint was resolution of edema at the macular center as determined by a masked reading center. Enrollment in the 2.0 μg/day group was discontinued early in the study.

At 24 months, macular edema completely resolved more often, compared to the SOC groups (54% vs 29%, respectively, P<0.05). VA significantly improved by at least 3 lines in 37% of FA-treated eyes compared to 14% of SOC eyes and significantly gained 3 lines of VA.¹⁴

The second study (Retisert DME 005) enrolled 197 adults with diffuse DME similar those recruited into the DME 002 study. Exclusion criteria were stricter in regards to glaucoma history, as subjects were excluded who had a history of uncontrolled IOP within the prior 12 months or IOP greater than 22 on no more than 1 ocular hypertension medication. The primary endpoint was resolution of retinal thickening at the macular center. Subjects were randomized to receive a 0.59 FA Retisert implant or SOC in a 2:1 ratio. At 36 months, complete resolution of edema was significantly greater in the FA group compared to SOC (58% vs 30%, respectively; P<0.001). VA also improved by greater than 3 lines (28% vs 15%, respectively).¹⁵

Ocular serious adverse events in both studies were notable and similar in the implanted eyes and were attributed to the ocular side effect profile of glucocorticoids. Significant IOP elevation developed in 32% and 35% of patients at 2 and 3 years, respectively. Trabeculectomy was required in 20% in the 002 study at 2 years and 28% in the 005 study at 3 years. Significant cataract progression occurred in 77% of phakic eyes by 2 years and up to 95% at 3 years. Rates of retinal detachment, endophthalmitis, and device explantation remained very low.^14-16

Ahmad et al. determined that pretreatment VA and postimplantation resolution of edema correlated with maximal postimplantation acuity while duration of diabetes and severity of DME both inversely correlated with posttreatment acuity. The pretreatment presence of large macular cysts was associated with greater reduction of central foveal thickness.¹⁷

MEDIDUR CLINICAL TRIALS IN DME

Based on the clinical results and safety profile observed in the Retisert OO2 and OO5 studies, the Medidur insert has entered phase 3 testing in DME. The Fluocinolone Acetonide in Diabetic Macular Edema (FAME) study is a randomized, double-masked, parallel group, dose-finding safety and efficacy study that compares the 0.5 μg/day and 0.2 μg/day injectable Medidur inserts with sham injection. The study includes 2 doses of FA, as the Retisert DME study provided safety and efficacy data for the 0.5 μg/day dose, but it is unknown if the 0.2 μg/day dose would be as effective but with an improved side effect profile.

The FAME study seeks to enroll 450 patients in 2 parallel trials (total 900 patients) worldwide. The objective is to determine superiority of the inserts groups compared to the sham-treated group, where the primary endpoint is based on VA, as was done for the previous Retisert trials. Additionally, overall retinopathy changes will be assessed using the ETDRS diabetic retinopathy grading scale. Secondary objectives include determining which is an optimal FA dose to treat DME and minimizing side effects.

SUMMARY

The Medidur FA sustained-release insert is now in pivotal trials to receive regulatory approval for DME. It benefits from the preclinical and clinical data established by the Retisert FA implant. However, the Medidur insert is being tested with lower release rates than previously available with Retisert or other inserts currently in studies and is being injected further back in the posterior segment. Medidur also has the advantage of an office-based delivery system. Future reports will establish if minimizing drug exposure (daily and cumulative release) can provide the long-term safety and efficacy of this insert in treating retinal diseases and if this system reduces steroid-induced side effects compared to those seen in previous Retisert trials. RP

REFERENCES

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