Vitrase Fun Facts: The role of the vitreous in diabetic retinopathy James Lewin, PharmD Postdoctoral Fellow/Vitrase Lead

The inspiration for this article came from an inquiry that I received in third month of my fellowship. I received an unsolicited request for medical information from a clinician regarding Vitrase (hyaluronidase injection) and the effect inducing posterior vitreous detachment (PVD). Although the lyophilized, ovine formulation of hyaluronidase (which is no longer being manufactured) was previously studied for the induction of PVD and the effect on progression of diabetic retinopathy, it was not FDAapproved for this use and ISTA is not conducting further studies in this population with the current formulation of Vitrase.1 The aim of this article is to describe the pathologic role of the vitreous gel in the development of diabetic retinopathy and to provide a brief overview of vitreolytic agents. This article does not represent a recommendation for the use of any of the pharmaceuticals or biologics named herein, and all opinions expressed in this article are those of the author and do not necessarily represent the views of ISTA or its employees. The evolution of technology has facilitated much advancement in ocular imaging tools, such as ocular coherence tomography (OCT), and has enabled researchers to establish an association between disorders of the vitreous body and the development of diabetic retinopathy.2 As time progresses, the vitreous liquefies and eventually pulls away or separates from the back of the eye where it is attached to the retina. This process is called PVD and is a common event that can occur in all individuals at some point later on in their life. Studies have demonstrated a clear increase in the prevalence of PVD with age.3 In general, interventions are not required for PVD unless the vitreous does not separate clearly from the retina (incomplete PVD). Incomplete PVD is a surrogate marker for vitreomacular adhesion (VMA), which can manifest as many retinal and macular disorders including but not limited to macular hole, age-related macular degeneration, as well as diabetic and cystoid macular edema. Although vitrectomy has been established as an option for inducing PVD and correcting VMA, this surgical approach is not always reliable and can be very expensive; furthermore, the use of non-invasive interventions could potentially reduce patient exposure to severe surgical complications. Researchers are investigating vitreolytic agents to induce PVD through vitreous liquefaction (liquefactants), vitreoretinal separation (interfactants), or both. At this time, there are no FDA-approved agents for treating PVD or VMA See Table 1. Table 1: Classification of vitreolytics that have either been tested or are currently under development.ab Interfactants Liquefactants Both Mechanisms Enzymatic Dispase Hyaluronidase Ocriplasmin Collagenase tPA Nattokinase Chondrotinase Nonenzymatic RGD peptides Vitreosolve a 2 Adapted from Schneider, et al b Abbreviations: RGD= Arginine-glycine-aspartate; tPA=Tissue plasminogen activator The recent submission of a Biological License Application (BLA) subsequent to successful Phase III clinical trial results with Ocriplasmin a truncated form of the human serine protease plasmin was another reason for deeming this article appropriate for the MAM Newsletter. The original BLA was

submitted by Thrombogenics in December 2011 for the treatment of symptomatic VMA including macular hole: the FDA has granted Ocriplasmin priority review status, and, as a result, Thrombogenics has withdrawn their original filing and announced on February 2, 2012 that they plan to re-submit a BLA in April 2012 in order to meet the FDA pre-approval inspection timelines. References: 1. Kuppermann BD, Mercado HQ, Graue-Wiechers F, et al. Effect of Intravitreous Hyaluronidase (Vitrase) on Progression of Diabetic Retinopathy in Humans. Invest Ophthalmol Vis Sci 2002;43: EAbstract 3865. Accessed March 2, 2012. 2. Schneider EW, Johnson MW. Emerging nonsurgical methods for the treatment of vitreomacular adhesion: a review. Clin Ophthalmol. 2011:5;1151-1165 3. Ang A, Poulson AV, Snead DRJ, et al. Posterior Vitreous Detachment: Current Concepts and Management. Medscape website. http://www.medscape.com/viewarticle/513226. Published September 27, 2005. Accessed March 1, 2012 4. ThromboGenics NV. ThromboGenics Announces that the FDA Intends to Grant Ocriplasmin Priority Review. ThromboGenics website. http://thrombogenics.com/wpcontent/uploads/2011/03/THR_02_Ocriplasmin-BLA-PriorityReview_Final_ENG.pdf. Published February 2, 2012. Accessed March 1, 2012