Age-related macular degeneration (AMD) is an eye disorder which in elderly people severely affects vision. Pharmaceutical research has already led to innovative therapies for AMD. Current projects could lead to even better therapies in the future.
Age-related macular degeneration (AMD) is an eye disorder which is characterised by the growth of new blood vessels under the retina. It is a degenerative condition of the macula (the central retina), which deprives the sensitive retinal tissue of oxygen and nutrients. As a result, central vision deteriorates. AMD varies widely in severity – in the worst cases, it causes a complete loss of central vision, making reading or driving impossible. Fortunately, macular degeneration does not cause total blindness, since it does not affect peripheral vision. AMD is classiﬁed as either wet (neovascular) or dry (non-neovascular). Eighty ﬁve per cent of patients with AMD suffer from the dry form. The wet form damages central vision more severely.
Based on the pattern of the blood vessel leakage, wet AMD can again be divided into three forms: predominantly classic, occult and minimally classic. These types occur when new vessels form to improve the blood supply to oxygen-deprived retinal tissue. However, the new vessels are very delicate and break easily, causing bleeding and damage to surrounding tissue. Wet AMD is responsible for the majority of cases of severe vision loss. Diagnosis is based upon indirect ophthalmoscopy, slit-lamp microscopy, and fundus photography to establish the presence pattern of AMD.
AMD may be caused by a variety of factors. Genetics, age, nutrition, smoking, and exposure to sunlight may all play a role. It is the most common cause of vision loss in developed countries in those 50 or older, and its prevalence increases with age. Approximately 15 million people have it in the US. In Europe, the number of people with AMD is estimated to be around 20 million.
Recently, investigators reported ﬁndings regarding altering amino-acid sequence variations in ﬁve members of the ﬁbulin gene family. Mutations in the ﬁbulin 5 gene were found in 1.7 per cent of patients with AMD. Many variations in other ﬁbulin genes were also found in these patients, and the evolutionary conservation of the affected residues suggests that several of these variations may also be involved in AMD.
There is no proven medical therapy for dry AMD. In the past, in selected patients with wet AMD, laser photocoagulation has been reported to be effective for sealing leaking or bleeding vessels. Unfortunately, laser photocoagulation does not restore lost vision, but it may prevent further loss. Recently, ocular photodynamic therapy (PDT) has proven to be effective in stopping abnormal blood vessel growth in patients with wet AMD. This new type of laser treatment uses a sensitive dye which is given by intravenous infusion 15 minutes before laser treatment of the affected eye. When activated by a non-heat producing laser of a speciﬁc wavelength (689 nm), the compound starts a chemical process that destroys abnormal blood vessels growing beneath the macula, leaving normal blood vessels unharmed.
Since the end of 2004, a new anti-angiogenesis product has been made available in the US. In September 2004, it was also ﬁled in the EU for the treatment of wet AMD. The newly developed molecule works by inhibiting the excessive growth of blood vessels behind the retina. The product is a pegylated anti-VEGF (vascular endothelial growth factor) aptamer that binds to and inhibits the growth factor, a protein that is important for blood vessel growth or angiogenesis and increased blood vessel permeability – two of the main processes seen in wet AMD. The VEGF-blocker may also be given in combination with PDT.
The newly developed medicine is injected directly into the eye. The intra-ocular injection route is a possible area of concern, as patients can ﬁnd it unpleasant or inconvenient. Therefore, education material has been developed for physicians and patients about the risk of an eye infection, endophthalmitis, and follow-ups after the injection. A phone call after three days and a patient visit one week later are recommended. Also, there will be long-term surveillance and follow-up because of the possibility of cardiovascular effects due to the inhibition of VEGF.
There are results from Phase 2/3 trials of two other molecules under development for age-related macular degeneration. One is a monoclonal antibody fragment for intraocular anti-angiogenic treatment and is in Phase 3 trials. The other approach constitutes a less invasive treatment, as it is given by an injection. Dosing during the study consisted of four weekly injections, with no further maintenance therapy. This compound is in Phase 2 and will in the future be tested with maintenance therapy, variations in dosing and/or combination treatment with PDT. Both compounds work by preventing the growth of new blood vessels under the retina. As clinical trials have to go on for at least one year to demonstrate preserved or improved vision after initiation of therapy, the launch of these new products cannot be expected before 2007.
Another investigational product for wet age-related macular degeneration is delivered behind the eye using a blunt-tipped, curved cannula. This approach does not puncture the eyeball, so it avoids the possible risk of intra-ocular infection and retinal detachment. However, the medicine may leak out through the incision made in the conjunctiva.
In 2004, two research groups reported the start of a Phase 1 trial of an intravenous VEGF antagonist in patients with wet AMD. Preclinical studies showed that the molecule inhibited the growth of new blood vessels when given intravenously as well as when administered directly into the eye.
In the US, another PDT molecule (SnET2) using a laser delivering light of a shorter wavelength (664 nm) is under priority review. Another study tests the safety and effectiveness of a steroid implant in preventing or slowing further vision loss in patients who cannot be treated with PDT.
There is also research underway for new drug delivery technologies. Investigators concentrate on biodegradable, controlled-release, intraocular drug delivery platforms. It is believed that biodegradable drug delivery would offer a superior method of targeting drugs to the back of the eye. Other positive features of such implants are the facts that they can be inserted using a relatively small needle under local anaesthesia and that their small size causes fewer traumas to the eye. The technology is versatile, allowing the design of different delivery durations and the application of a wide variety of compounds.
New research into the effects of the protein TIMP-3 (tissue inhibitor of metalloproteinases-3) could lead to the development of new medicines to treat age-related macular degeneration. TIMP-3 binds to the VEGF-2 receptor, stopping vascular endothelial factor binding and preventing the receptor becoming activated to cause excessive blood vessel growth. Further compounds that are efﬁcient metalloproteinase inhibitors may also be suitable for AMD treatment.
In recent years the gene silencing technique, RNA interference (RNAi), has generated considerable interest. First observed in 1998, RNAi is a cellular process by which cells silence the expression of certain genes, but scientists will need to overcome the difﬁculties of delivery and stability. Two research groups with RNAi projects are looking into the possibility of silencing the genes for VEGF in AMD, and initial results were expected in 2005. Once validaded, this new approach will open up for research in new medicines.