REVOLUTION IN VITREORETINAL TREATMENT

[caption id='attachment_1662' align='alignright' width='400' caption='VMA is an increasingly recognised sight-threatening disease in which the adhesion between the vitreous and the macula does not weaken sufficiently to allow for separation of vitreous1'][/caption]

Some 30 years ago, Désiré Collen MD, PhD, of Katholieke Universiteit Leuven, Belgium, revolutionised cardiovascular and stroke care with tissue plasminogen activator, the first major clot breaking medicine. “Until that drug became available, most people died of heart attacks,†says Patrik De Haes MD, chief executive officer of ThromboGenics NV, which Dr Collen founded in Leuven.

Today, ThromboGenics may be at the brink of a similar revolution in vitreoretinal treatment with Ocriplasmin. Following successful Phase III clinical trials, the firm submitted applications to the European Medicines Agency and the US Food and Drug Administration (FDA) for treating symptomatic vitreomacular adhesion (VMA), including macular hole. If approved, it will be the first pharmacological treatment available for this indication, which the firm estimates may affect as many as 500,000 patients annually in the US and Europe.

The FDA indicated its intent to grant Ocriplasmin priority review status, so ThromboGenics expects approval in the US later this year. If the EMA grants marketing authorisation, the firm anticipates an early 2013 rollout in the major EU markets, says Dr De Haes. There is an ongoing phase II study of Ocriplasmin for wet age-related macular degeneration and further trials are planned in diabetic retinopathy. VMAs have been suggested to play a role in many retinal diseases.

Minimally invasive therapy

[caption id='attachment_1662' align='alignright' width='400' caption='VMA is an increasingly recognised sight-threatening disease in which the adhesion between the vitreous and the macula does not weaken sufficiently to allow for separation of vitreous1'][/caption]

While liquefaction and separation of the vitreous from the retina is part of the normal ageing process, sometimes the separation is incomplete and the vitreous continues to adhere strongly to the macula. As the vitreous continues its collapse and pulls on the retina, the resulting traction can lead to symptoms including metamorphosia, decreased visual acuity and central vision defects, says Steve Pakola MD, ThromboGenics’ chief medical officer.

Symptomatic VMA can resolve on its own if the adhesion separates. If it doesn’t, prolonged traction may progress, further impairing vision and possibly leading to macular holes and permanent retinal damage. But the only treatment option today is vitrectomy, which carries its own significant treatment burden and risk of complications. As a result, many patients with vision loss are left untreated, Dr Pakola notes. “You wait until the benefits clearly outweigh the risks.â€

As a well-tolerated, minimally-invasive treatment option, Ocriplasmin shifts the risk-benefit balance, allowing not only treatment of patients with significant visual loss or macular hole, but also early cases before they progress, Dr Pakola says. The compound is a truncated form of human plasmin produced by recombinant DNA technology. Injected into the eye, Ocriplasmin targets laminin, fibronectin and collagen, which induces both vitreous liquefaction and separation of the vitreous at the vitreoretinal interface.

The resolution of VMA and closure of full thickness macular holes can be quick which can lead to significant visual acuity. In Phase III clinical trials, ~30 per cent of 188 patients with vitreomacular traction treated with a single injection of Ocriplasmin experienced VMA resolution at 28 days after treatment, compared with just 7.7 per cent of patients receiving a placebo injection (p<0.001), according to data presented at the 2011 American Academy of Ophthalmology meeting by Pravin U Dugel MD of the University of Southern California, Los Angeles, US. Similarly, ~40 per cent of 106 patients with full thickness macular hole, had hole closure at 28 days compared with 10.6 per cent of placebo patients (p<0.001). The response rates to a single injection of Ocriplasmin were even higher (~58 per cent) for macular holes smaller than 250 microns compared with 16.0 per cent for the placebo-group (p<0.001)

More importantly, all of the Ocriplasmin treated full thickness macular hole patients maintained their hole closure at six months, Dr Dugel reported. These patients also noticed a significant improvement in their visual acuity, with the percentage gaining three lines or more increasing from 2.3 per cent at day seven post injection to 51.2 per cent at six months. Dr Dugel noted that the study lasted only six months, but if it continued he believes the gains would likely continue for a year or more, a result he has observed with his own patients.

There was no notable difference in the incidence of serious adverse events between Ocriplasmin-treated and placebo-treated patients. Most of the adverse events noticed were limited to the first seven days after treatment and were mostly transient resolving within weeks after the injection, Dr Dugel said. There were no retinal tears and one case (0.4 per cent) of retinal detachment noted at day 28 in the Ocriplasmin group.

Ocriplasmin’s success has prompted ThromboGenics to switch its research and development focus to ophthalmology. “We are committed to addressing unmet needs in ophthalmology,†Dr De Haes says.

ThromboGenics is focused on commercialising Ocriplasmin on its own. Retinal diseases are treated by a small group of specialists consisting of ~4,000 physicians in the US and Europe, Dr De Haes says. “As a small company with good funding we can build a manageable team to fully support the launch of the product on our own. We continue to invest into commercial organisation and have brought on board an experienced group of executives in 2011 to build and lead our commercial efforts,†Dr De Haes concluded.

Picture references:

1. Schneider EW, Johnson MW. Emerging nonsurgical methods for the treatment of vitreomacular adhesion: a review. Clin Ophthalmol. 2011;5:1151-1165.

2. Gallemore RP, Jumper JM, McCuen BW II, Jaffe GJ, Postel EA, Toth CA. Diagnosis of vitreoretinal adhesions in macular disease with optical coherence tomography. Retina. 2000;20:115-120.

3. Mitry D, Fleck BW, Wright AF, Campbell H, Charteris DG. Pathogenesis of rhegmatogenous retinal detachment: predisposing anatomy and cell biology. Retina. 2010;30:1561-1572.

4. VMT image used with permission of Ferdinando Bottoni, MD, FEBO. Eye Clinic, Department of Clinical Science “Luigi Saccoâ€, Sacco Hospital, University of Milan, Milan, Italy.