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Eye disease

ThromboGenics is working to satisfy what it believes is a substantial unmet clinical need for a safer and more effective method of inducing posterior vitreous detachment (PVD), which is considered beneficial in patients with numerous retinal conditions.

The surgical procedure used to achieve a PVD is called a vitrectomy (where the vitreous in the eye is separated from the retina), and is performed to clear blood and debris from the eye, to remove scar tissue, or to alleviate traction on the retina. Blood, inflammatory cells, debris, and scar tissue obscure light as it passes through the eye to the retina, resulting in blurred vision. See figure

PVD has been shown to be beneficial in preventing blinding eye diseases, such as macular hole (MH), diabetic macular edema (DME), diabetic retinopathy (DR), and age-related macular degeneration (AMD). It is thought that these disorders rely on the connection of the vitreous to the retina. Therefore, by separating the vitreous from the retina in a non-surgical way, microplasmin,as a proteolytic enzyme, could prevent the development or progression of these important “back of the eye” diseases. DR and AMD each represent markets of over $1 billion annually. ThromboGenics has been granted FDA orphan drug designation for microplasmin use in pediatric eye surgery.

Vitrectomy

ThromboGenics has successfully completed a Phase IIa trial (MIVI-I trial) to assess the safety and efficacy of microplasmin as a surgical adjunct for vitrectomy. The MIVI-I study was an open label, dose-ranging trial evaluating the effect of intraocular injection of recombinant microplasmin conducted in 60 patients undergoing vitrectomy. The trial was performed at centers in Belgium, the Netherlands and Germany. Results presented at the Association of Research in Vision and Ophthalmology (ARVO) and Euretina congresses in May 2007 showed that microplasmin was well-tolerated and can in certain cases induce spontaneous PVD without the need for suction at all before vitrectomy. The ability to achieve spontaneous PVD was most evident after seven days exposure, in which five out of 10 patients had a total PVD before vitrectomy. This data supports the view that microplasmin alone may be sufficient to induce a PVD. In addition, most patients in the study were able to have PVD induced with relatively low amounts of suction and without the need for mechanical intervention.

Following these positive results, ThromboGenics began the MIVI-III trial. This trial is a Phase IIb multi-center, randomized, placebo-controlled, double-masked, dose-ranging clinical trial evaluating three doses of microplasmin (25, 75 and 125 μg) versus placebo in 120 patients scheduled for vitrectomy.  The trial is taking place across 19 sites throughout the United States and is assessing the safety and efficacy of microplasmin intravitreal injection 7 days prior to vitrectomy.  Top-line, unmasked results of this trial are expected by mid 2008. The results of this trial are expected to allow dose selection for subsequent Phase III clinical development.

Vitreomacular traction

The MIVI-IIT trial aims to evaluate the safety and efficacy of microplasmin for the treatment of vitreomacular traction, including macular holes. Vitreomacular traction is a condition in which the vitreous gel has an abnormally strong adhesion to the retina that could lead to decreased or distorted central vision. These conditions are currently treated by surgical vitrectomy to release the traction. Therefore, a drug that could facilitate the induction of PVD or induce spontaneous PVD may be able to relieve the traction or prevent the need for surgery. MIVI-IIT is a Phase II, sham injection controlled (patient is led to believe he is receiving the injection), dose ascending (75, 125 µg) trial. A total of 30 patients across two sites in Europe were recruited. Top-line results from the Phase II MIVI-IIT trial were presented at the American Society of Retina Specialists (ASRS) in December 2007 and have recently been published*. The data from this study demonstrated benefits from therapy compared with sham, with nine of the 24 microplasmin treated patients seeing resolution of their vitreomacular traction (including macular hole closure in two of the four macular hole cases) without the need for vitrectomy. In contrast, none of the six sham injected patients had resolution of their vitreomacular traction (including two patients with macular hole). The trial also showed that microplasmin therapy was well tolerated. Given the excellent tolerability of microplasmin in the trial to date, it has been decided to recruit a further 15 patients (12 treated and three sham) to evaluate a higher 175 µg dose of the product to determine if the higher dose might provide additional positive clinical outcomes. Completion of enrolment in the additional cohort has finished, with top-line results anticipated by mid 2008.

* Macular Surgery and Enzymatic Manipulation of the Vitreous Cavity: An Introduction to Chemical Vitrectomy.

   Quiram, P.A. and Goldenberg, D. Retinal Physician, March 2008.

Diabetic retinopathy

ThromboGenics has also started a MIVI-II (DME) Phase IIa trial in Europe to evaluate microplasmin injection for the non-surgical treatment of Diabetic Macular Edema, a form of Diabetic Retinopathy. MIVI-II (DME) is a sham injection controlled, dose ascending (25, 75, 125 µg) trial evaluating the safety and efficacy of microplasmin in 60 patients across eight sites in Europe. Completion of enrolment in MIVI-II is expected by end 2008.

For an overview of the different trials, please visit www.clinicaltrials.gov