A Clear View

C&I Issue 10, 2007

The primary cause of vision loss in the over 50s, age-related macular degeneration (AMD) is the leading cause of blindness in the UK and the developed world. By 2020, some estimates suggest as many as 8m people over 65 years could suffer from the disease. In the UK alone, there are at least 26 000 new cases of wet AMD – the most severe form of the disease – each year and up to 250 000 people are thought to have the disease although the real number could be much higher. AMD-related costs account for around £2.5bn/year, according to the Royal National Institute of the Blind (RNIB).

All patients go blind unless treated, but currently available NHS treatments are suitable for only about a quarter of patients. New drugs that halt vision loss and even restore sight have recently hit the market. But reluctance by Primary Care Trusts (PCTs) to pay for them means that patients must either stump up the cash themselves or go blind. And with a rising elderly population, the blind burden on the health and social services – already amounting to millions – is only going to get worse.

Progressive disease
AMD is a chronic progressive disease of the macula, the central portion of the retina, that results in loss of central vision. Dry (atrophic) AMD is the most common form and occurs when cells in the retina fail to function properly, degrade gradually and die. Over time, dry AMD can develop into the more severe wet (neovascular) AMD. This is caused by new abnormal blood vessels that leak blood and fluid into the retina, damaging the macula. Although wet AMD accounts for only about 10% of AMD cases, it progresses more rapidly and is responsible for 90% of blindness caused by the disease.

The NHS currently offers two treatments that aim to halt or slow the progression of abnormal blood vessels in wet AMD: laser photocoagulation or photodynamic therapy. However, only about 20-25% of patients are suitable for either treatment, both of which cause some damage to surrounding tissue. Safer, more effective, treatments are sorely needed.

The good news is that two new drugs that can halt vision loss and even improve sight have recently been approved in Europe and are suitable for most patients. The first to hit the market was Pfizer’s Macugen, approved by the European Medicines Agency (EMEA) in February 2005. This was followed by Novartis/Genentech’s Lucentis, which was approved in the EU in January this year.

Both drugs inhibit VEGF, an essential signalling protein responsible for the formation of new blood vessels and leakage. But Macugen (pegaptanib), a single strand of nucleic acid, targets only one VEGF isoform, whereas Lucentis (ranibizumab), a partially humanised therapeutic antibody fragment, is non-selective.

As well as its role in wet AMD, VEGF plays a vital role throughout the body, including a protective role in cardiovascular disease and diabetes. As a result, knocking out VEGF completely can cause cardiovascular and other side effects, and there is a four-fold risk of stroke in a small number of patients receiving higher doses of Lucentis. However, Lucentis has up to 40% chance of improving sight in newly diagnosed patients, compared with 20% for Macugen, according to Barbara McLaughlan, campaigns manager at RNIB.

Big demand
Despite requiring frequent eye injections, patients are clamouring for the drugs. Sales of Lucentis reached $380m for the remainder of 2006 after its US approval in June, despite its potential side effects.

Some patients are even risking their health with untested AMD treatments, with some doctors prescribing off-label small amounts of Genentech’s Avastin, a bowel cancer drug that seems to have a similar but weaker effect as Lucentis. Avastin (bevacizumab), a monoclonal antibody, non-selectively inhibits all VEGF isoforms and is thought to be much cheaper, with prices quoted ranging from £500 to £1500, according to McLaughlan. In February 2007, health secretary Patricia Hewitt urged manufacturer Genentech and marketer Roche to apply for a licence for Avastin to treat AMD so that NICE can evaluate it for NHS use. However, Avastin has not been tested for wet AMD in randomised controlled trials, and the companies say, with Lucentis already on the market, they have no plans to develop it for the disease.

The potential market for AMD is sizeable, with Novartis, Pfizer and Bayer as well as a host of smaller companies with drugs in development (see box). Most of the novel treatments, however, are years away, leaving Macugen and Lucentis the best option for patients.

NHS: pay up or go blind
Unfortunately, 90% of PCTs are refusing to pay for Macugen or Lucentis until NICE has issued clinical guidance later this year, according to the RNIB. ‘It is essential that new and clinically proven treatments that are licensed for use are reimbursed by governments with minimal delay,’ says Steve Winyard, head of public policy at RNIB.

‘Denying people treatment is really not acceptable,’ says McLaughlan. ‘Quite apart from the moral imperative of making sure that you don’t let people go blind, a whole range of costs need to be taken into account.’

Wet AMD patients have about a third of the ability of people with normal visual function and are unable to read, write, drive or recognise faces, and are twice as likely to experience depression. As a result, there are significant public health implications and enormous strain on healthcare budgets. ‘Patients with wet AMD, if they go blind, have eight times higher use of health resources than patients who don’t have the condition,’ says McLaughlan.

As well as inpatient and outpatient expenses, home health visits and nursing care, there are social services costs, not to mention the effect on informal carers, as well as work absence and lost productivity. In the UK, this average yearly cost amounts to about £7800 per newly diagnosed patient, according to Sorrel Wolowacz, senior health economist at RTI Health Solutions.

Although the Department of Health has issued several statements saying that the absence of NICE guidance is no reason to refuse treatment, PCTs are always able to argue that a certain drug does not fit their funding priorities, explains McLaughlan.

Increasing drug costs
The total cost of PCT treatment, including appointments and angiograms, is estimated at £7400 per patient, says Wolowacz. In comparison, the average cost of Macugen treatment and associated staffing and monitoring etc is likely to be £8700 per patient, but is expected to save an estimated average of £5800 in reduced costs of services, she continues. Although initially more expensive, Macugen is suitable for the majority of patients, saving the government much more overall.

The price of Lucentis has not yet been declared in the UK, but a highly speculative estimate puts the total yearly costs of treatment at about £27 600, says Wolowacz. And with the cost of developing a new drug averaging over $800m, new treatments in the pipeline are unlikely to be cheap once they reach the market. Patients could continue to be denied effective treatments if health authorities don’t adopt a broader approach to saving money.

‘My personal view is that [PCT refusal] is due to budget constraints, and the fact that although the cost of treatment is incurred by the PCT, the bulk of cost savings are realised by other funding sectors, for example reduced residential care, housing benefit and social security benefits,’ says Wolowacz.

NICE guidance is not expected until October 2007, after which there will be a three month implementation phase, unless there is an appeal.

Until then, consultants must submit funding requests on a case-by-case basis, which often takes longer than the three months after which many patients lose their sight. Moreover, most applications go through exceptionality committees that have very restrictive rules. ‘Those rules in most cases constitute a blanket ban because they say you have to prove that a patient would benefit over and above other patients and that a patient doesn’t belong to a big group of patients,’ says McLaughlan. ‘It’s a huge problem.’

With wet AMD the biggest cause of sight loss, the provision of Macugen and Lucentis on the NHS could reduce the number of partially sighted or blind people by half. ‘This would represent a major step towards achieving the UK Government’s Vision 2020 objective of eliminating avoidable sight loss by 2020,’ says the RNIB and the Macular Disease Society in their submission to NICE.

Blind hope
This month, UK researchers began the world’s first gene therapy trials to try to restore eyesight. Involving adults and children with a rare type of inherited retinal degeneration called Leber’s congenital amaurosis (LCA), for which there are currently no effective treatments, the technique inserts healthy copies of the malfunctioning RPE5 gene responsible for the condition into the cells of the retina.

The results of the trials in humans may not be known for many months, according to researchers carrying out the trial at University College London (UCL) and Moorfields Eye Hospital. However, in previous work with dogs, the defect was restored to the extent they were able to walk through a maze without difficulty, something that would have been impossible before the surgery.

If human trials are successful, the approach could potentially be applied more widely, says lead researcher Robin Ali at UCL’s Institute of Ophthalmology. ‘There are many forms of retinal degeneration, meaning the use of gene therapy treatments must be individually developed then tested in separate clinical trails specifically for that disease. However, the results from this first human trial are likely to provide an important basis for many gene therapy protocols in the future.’

Selected AMD treatments in the pipeline

  • German firm Retina Implant is developing a retinal chip in which tiny light-sensitive photodiodes take over the function of damaged photoreceptor cells. The electronic chip, which is implanted under the retina, restored some vision in a pilot study in people (C&I 2006, 6, 9).
  • OcuCure Therapeutics is developing topical eye drops based on a selective tubulin inhibitor – a type of vascular targeting agent – that eliminates newly formed blood vessels and stops new ones forming. Animal studies show the compound reaches the back of the eye in clinically significant concentrations without toxicity (C&I 2006, 22, 10).
  • In March, Bayer Healthcare and Regeneron Pharmaceuticals reported positive Phase 2 data for their VEGF Trap-Eye, a non-selective, soluble VEGF receptor fusion protein. The hope is that the product will require less frequent dosing than Macugen or Lucentis.
  • In March, researchers in the US reported that neural progenitor cells derived from human foetal stem cells protected vision in rats (PloS ONE 2007, 2(3), e338).
  • In February, Novartis and Fovea Pharmaceuticals announced a collaboration to develop Rod derived Cone Viability Factor (RdCVF) to prevent cell death in retinal degenerative conditions.
  • In February, SR Pharma and Quark Biotech started Pfizer-funded phase 1 trials of RTP-801i, a small interfering RNA product.
  • University of Southern California researchers are testing an artificial retina in people. An array of electrodes is attached to the retina and used in conjunction with an external camera and video system to provide rudimentary sight.

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