My first impression of the ARVO meeting: hot, humid, exciting. Approximately 12,000 vision researchers, ophthalmologists, and industry representatives descended on the Fort Lauderdale convention center for a week of information exchange. The meeting had everything from studies of the embryonic eye to studies of vision in the elderly.
Perhaps the most satisfying therapeutic story for diabetes involved the inhibition of the growth of new blood vessels – a process called angiogenesis. As I mentioned in my last post, high glucose causes a number of problems leading to thickening of the capillary membrane around the retina. This forms the basis for Diabetic Retinopathy (DR), one of the greatest causes of blindness in the developed world. It is assumed that thickening of the capillary membrane decreases oxygen permeability and leads to a state of tissue hypoxia. The tissue responds by calling out for new blood vessels. These new blood vessels push aside photoreceptors and leak fluid all over the retinal space. Blocking the growth of these vessels has been a goal of researchers for some time.
The search for drugs which block new vessel growth has been a “holy grail” of sorts for cancer researchers since the 1980s. This is because tumors release signals that attract growing blood vessels to supply additional nutrients to assist in tumor growth. It has taken quite some time (due to differences between the mouse model and human biology) but now we have arrived. It is clear that the major angiogenic signal is produced by a hormone called vascular endothelial growth factor (VEGF). The vascular endothelial cells create the tube that is the blood vessel. When VEGF binds to receptors found on the surface of a localized group of these cells they begin to break up and leave the tube. At first there is a short competition to see who will be the lead cell and who will follow. Then the lead cell (called the tip cell) begins to migrate towards the angiogenic signal with the following cells dividing to begin to create a new blood vessel. VEGF regulates most aspects of this complicated process, suggesting that this would be a good therapeutic target.
It was not until 2004 that the first VEGF inhibitor hit the market. Today the most popular forms of this therapy include Leucentis and Avastin. A host of newer molecules are making their way through clinical trials. All of them work by binding to VEGF molecules and keeping them from binding to VEGF receptors. They were originally approved for Age-related Macular Degeneration (AMD) and only fairly recently have been applied to DR. The results have been quite promising.
Here are the results from one study: the DA VINCI trial – chosen for the simple reason that they had nice handouts with all of the information so that I could write this at my leisure. All of the DR clinical trial data that I saw was comparable.
The study I am going to describe involves a synthetic protein that sort of looks like an antibody. Think of an antibody like the letter “Y”. The two top ends of the Y bind to a specific target while the base of the Y holds everything together. The linkage of two binding sites gives the molecule a lot of flexibility and increases its ability to bind to things. Researchers at Bayer Pharmaceuticals made use of this flexible structure; substituting binding regions of the VEGF receptor for the top parts of the Y while leaving the base of the Y intact. We have a name for this sort of construct. We call it an Fc fusion protein. At any rate, they called this new molecule VEGF Trap-Eye or VTE (not my favorite name).
This was a phase II clinical trial which means that the drug had already passed human safety tests and was now being evaluated in a small population for efficacy. Two hundred and twenty one patients were randomized to receive either laser photocoagulation or one of 4 doses of VTE. I should mention that laser photocoagulation is a rather clumsy method in which leaky blood vessels are closed by burning them shut. That was the state of the art treatment for many years. All patients had macular edema (water around the most critical visual region of the eye – the macula). The average age of the patients ranged from 60 to 64 with a slight preponderance of males (55 – 65%). The average HbA1c for each patient group ranged from 7.8 to 8.1. Several had earlier injections of either a different VEGF inhibitor or a steroid some time in the past however these were pretty much distributed equally among the groups. VTE was administered by intravitreous injection. This is fairly yucky – I saw several movies of surgeries and the needle is just poked right into the eye. Presumably patients are anesthetized. Patients were evaluated monthly and the report ended at the 6 month time point.
Improvements in visual acuity are sometimes reported in numbers of letters gained using the EDTRS system. This is the standard eye chart you see when you go to get your eyes checked. Each line has 5 letters and each subsequent line of letters gets smaller and smaller. The laser photocoagulation group gained an average of 2.5 letters. The various VTE dosing groups gained averages ranging from 8.5 – 11.4 letters. This is about two extra lines smaller and amounts to a pretty significant improvement in visual acuity.
Adverse events were present and need to be mentioned. These include conjunctival hemorrhage (excessive bleeding), increased intraocular pressure (think glaucoma), eye pain (that one is pretty obvious), ocular hypertension (increased blood pressure but specifically in the eye), and vitreous floaters (visible shapes that occlude your vision floating in the body of the eye). These were about the same for all groups including the laser coagulation group. There was a small increase in the number of people who developed increased intraocular pressure in all VTE groups suggesting to me that this one might be different from the laser treatment but then the laser group had more serious problems than the VTE groups.
All in all, this looks very promising. It is not a cure but it may give some folks enough vision to read – maybe even to drive. Sweet.