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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. See figure

PVD has been shown to be beneficial in 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.

Vitreomacular adhesion (traction) & vitrectomy

Vitreomacular adhesion (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. Vitreomacular adhesion  can also lead to sight threatening conditions such as macular holes or macular edema. 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 adhesion or prevent the need for surgery.

After successful completion of a Phase IIa trial (MIVI I), ThromboGenics proceeded with a Phase IIb trial (MIVI-IIT), which aims to evaluate the safety and efficacy of microplasmin for the treatment of vitreomacular traction, including macular holes. MIVI-IIT is a sham (pretend) injection controlled, dose ascending trial. The first three cohorts evaluated single injection of 75, 125 and 175 µg microplasmin, while the 4th cohort is evaluating up to 3 injections of 125 µg microplasmin. A total of 60 (48 treated and 12 sham) patients across three sites in Europe were recruited. Unmasked, 28 day follow-up results are available and have been presented at scientific congresses. Study drug has been well tolerated. Further, in patients treated with 125 µg, over 1/3rd of the microplasmin-treated patients had resolution of their vitreomacular traction (including macular hole closure in 3 of the 8 macular hole cases) within 28 days without the need for vitrectomy. In contrast, only 1 of the 12 sham injected patients had resolution of their vitreomacular traction in the same time period.

Following these encouraging results, ThromboGenics began the MIVI-III trial. This trial was 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 125 patients scheduled for vitrectomy. The trial took place across 19 sites throughout the United States and assessed the safety and efficacy of microplasmin intravitreal injection 7 days prior to vitrectomy.  The study showed that microplasmin was well tolerated. The trial also showed a clear dose response curve with the highest 125 μg dose of microplasmin delivering the best results. In this group, 30% of patients had resolution of their underlying disease and therefore did not need a vitrectomy (surgical intervention) for the indication for which they were being treated. In addition, use of microplasmin was associated with a reduced amount and duration of suction needed to achieve a PVD in patients who progressed to surgical intervention, compared to placebo. The results from this study were presented in June 2008 at the World Ophthalmology Congress in Hong Kong.

ThromboGenics previously announced plans  to proceed into Phase III clinical development of microplasmin based on the encouraging results. The two pivotal trials in the current Phase III program (MIVI-TRUST, Microplasmin IntraVitreous Injection - Traction Release without Surgical Treatment) are multi-centre, randomized, placebo controlled, double-masked trials which will evaluate 125μg of microplasmin versus placebo in the intravitreal treatment of patients with focal vitreomacular adhesion. The trials will enroll approximately 320 patients each across approximately 40 centres in the United States (TG-MV-006) and 40 centres in Europe and North America (TG-MV-007).

The primary endpoint of both trials is the non-surgical resolution of focal vitreomacular adhesion after one month. Additional measures of efficacy and safety will also be assessed at various intervals over six months in both studies. Both trials have recently been initiated; please refer to the press release for more information.

Physicians and Investigators interested in participating in the Phase III microplasmin studies, please contact the MIVI-TRUST team. For more information on MIVI-TRUST please refer to http://www.clinicaltrials.gov.

* 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 at end 2008.

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