LONDON – A head-to-head study funded by the UK Department of Health has found Avastin and Lucentis are equally effective and safe in treating wet age-related macular degeneration (AMD), and that using Avastin off-label in this indication would save the National Health Service £84.5 million (US$136.9 million) per year.

The research backs up the findings of an equivalent U.S. National Institutes of Health study, Comparison of AMD Treatment Trials (CATT). Data from both U.S. and UK studies were presented at the Association for Research in Vision and Ophthalmology annual conference in Miami on Sunday.

"Lucentis and Avastin have similar effectiveness," said Usha Chakravarthy, professor of ophthalmology and vision sciences at Queen's University, Belfast, who is principal investigator on the UK study IVAN (A randomized controlled trial of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularization).

In the 23-center trial, 610 patients were randomized to receive either the cancer drug Avastin (bevacizumab) or its counterpart Lucentis (ranibizumab). "Regardless of the drug received, or treating monthly or as needed, sight in the effected eye improved by between one or two lines on a standard eye test," Chakravarthy said.

The potential saving arises not only because Avastin costs £60 per injection and Lucentis £700, but also because when administered on an as-needed basis, Avastin was dosed on average seven times per year, compared to the once-monthly dosing recommended on the Lucentis label.

The one-year results from the IVAN trial confirmed the two-year data from the CATT study involving 1,107 patients, which concluded Avastin and Lucentis had similar effects on visual acuity. Although there were more serious adverse events with Avastin, there were no differences between the two vascular epithelial growth factor (VEGF) inhibitors in rates of death, stroke or heart attack.

The data come at an awkward moment for Novartis AG, of Basel, Switzerland, the holder of all non-U.S. rights to Lucentis, which last month began a legal action to stop some UK health trusts from using Avastin in place of Lucentis. The company argued that using an unlicensed drug when there is a licensed alternative undermines the whole regulatory process for medicines.

Although the two antibody drugs have the same mode of action, they do have different properties, with Avastin designed to be administered intravenously and to stay in the bloodstream, whereas Lucentis is delivered by intraocular injection and is rapidly cleared from the system. Novartis attributed the higher rates of serious adverse events in Avastin-treated patients seen in the CATT trial to those different properties, and to the risk of contamination when a single dose of Avastin for treating cancer is split into multiple doses for use in AMD.

Commenting on the two-year CATT results, Tim Wright, global head of development at Novartis, said, "This data adds to the growing body evidence suggesting that the overall risk of serious ocular and systemic side effects is higher with unlicensed intravitreal [Avastin] compared to Lucentis." He added that the "apparent differential safety risks" between Avastin and Lucentis "may be due to differences in the molecules and their commercial formulation."

Wright further charged that the lack of any evidence of an increase in death or stroke in patients treated with Avastin is because CATT and IVAN are not powered to uncover that risk.

In fact, the one-year IVAN data showed a slightly higher rate of heart attacks and strokes among people treated with Lucentis. However, that was not observed in CATT, and when the results of the two trials were combined, no difference in heart attacks or strokes was seen between the two drugs.

There remains the slightly higher rate of other serious adverse events in patients receiving Avastin across both trials. But while Novartis points the finger firmly in the direction of systemic side effects, Chakravarthy said the adverse events could not be attributed directly to Avastin, since such events were more common in patients treated less frequently, and they arose mainly from hospitalizations for a wide variety of causes not previously associated with either drug.

In their journal paper, the CATT researchers agreed with that and wrote, "The interpretation of the persistence of higher rates of serious adverse events with [Avastin] is uncertain because of the lack of specificity to conditions associated with the inhibition of VEGF." Indeed, the very different readings of the safety data by the researchers who conducted the CATT study and by Novartis, makes it hard to tell they are discussing the same trial.

Ophthalmologists began using Avastin to treat AMD following positive clinical trial results for Lucentis, and according to the CATT research paper, Avastin rapidly became the most commonly used drug for wet AMD in the U.S.

While Genentech Inc., as developer of both drugs, has no interest in head-to-head studies, the huge price differential and widespread off-label use prompted the UK Department of Health to take the unusual step of funding an efficacy and safety trial of two licensed drugs. Other Avastin/Lucentis comparison trials are in train in France, Germany, the Netherlands, Australia and Brazil.

Though Novartis will continue to make the argument it is wrong to use an unlicensed drug when a licensed drug is available, the driver here is cost. As the CATT researchers noted, in 2010 Lucentis accounted for almost 10 percent of the entire Medicare Part B drug budget – and was the single largest item of expenditure. As treatment continues indefinitely, the financial cost can only increase. The choice of Avastin or Lucentis has to balance the comparable effects on vision and the possibility of a different side effect profile, with the fact that there is a 40-fold difference in cost per dose in the U.S.

The uncertainty over the comparative safety of Avastin and Lucentis has unnerved patients' groups.

Helen Jackman, chief executive of the UK Macular Disease Society, said there needs to be a national solution to the uncertainty. "If Avastin is not as safe as Lucentis, no one should be using it. If it is as good, perhaps everyone should be using it," she said in a statement last month calling on the government to resolve the question of which drug should be used.