LONDON – The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has had another Glybera moment, turning down the rare disease drug Raxone (idebenone) by a narrow majority, despite the rapporteurs on an expert committee recommending approval of the drug, which treats a hereditary cause of blindness.

"We're not disclosing the size of the majority against, but we do know, and I can confirm it's very narrow," Thomas Meier, CEO of Raxone's developer Santhera Pharmaceuticals AG, told BioWorld Today.

Raxone is a treatment for Leber's hereditary optic neuropathy (LHON) a mitochondrial disorder that affects one in 50,000. Inevitably in a rare disease, the number of patients taking part in the randomized, placebo-controlled trial that formed the basis of the submission was low, at 82. However, Meier said there was a clinical effect and this was statistically significant in a subgroup of 28 patients who had most recently been diagnosed.

"In the rapporteurs' view, sufficient data had been provided in this very rare disease, demonstrating a consistent and significant clinical benefit in LHON, in patients in whom the medical need was most urgent and the probability of benefit the highest," Meier said.

LHON typically presents in young adults, mainly males, as painless loss of vision, leading to blindness within a few months. While patients who were almost completely blind on entering the trial recovered sufficiently to read at least five letters on a standard eye chart, those with less-advanced disease who had residual vision were significantly protected against further disease progression.

Although the effect of treatment on the 28-patient subgroup was clinically relevant and consistent with data published in the literature, Meier said the CHMP expressed concerns that there were statistical outliers. Given there were no safety concerns, Meier said the best way to address that is through post-approval surveillance. "To gain more data, we have proposed a patient registry to collect data in the real world," he said.

Liestal, Switzerland-based Santhera has asked for the file for Raxone to be re-examined. "What we intend to re-emphasize is the importance of the post-approval commitments, the clear medical effect and the high medical need," Meier said.

He noted that it is hard for patients to make their views known to the EMA because impaired vision and blindness limits their use of the Internet and other forms of communication.

The case of Raxone has strong echoes of Glybera (alipogene tiparvovec), a gene therapy for the ultra-rare inherited disorder, lipoprotein lipase deficiency, which was turned down three times by the CHMP on the grounds that there was not enough data to demonstrate clinical benefit. The product, developed by uniQure BV, of Amsterdam, the Netherlands, finally was pushed over the finish line in November 2012 after the European Commission had taken the unprecedented step of refusing to rubber stamp the CHMP's recommendation that it should not be approved and told the committee to think again. When the CHMP again voted against, the EMA took an internal decision to review Glybera for a fourth time.

Like Raxone, there was evidence of individual clinical benefit in the 27 patients that took part in the Phase III trial of Glybera and with no safety concerns, the product eventually was given conditional approval, allowing further data to accumulate.

Glybera's protracted route to approval appeared to have prompted the EMA to modify its view of how clinical benefit should be weighed in rare diseases with high unmet medical need, where there are not enough patients to deliver statistically significant trial results. Now, the decision on Raxone calls into question if the CHMP has learned anything from its Glybera embarrassment. (See BioWorld Today, July 25, 2012.)

Raxone works by overriding mutations in mitochondrial DNA that cause faults in electron transport, inhibiting production of the cellular energy source, ATP. In LHON, the lack of ATP leads to oxidative stress and degeneration of the nerve cells in the retina and optic nerve. The compound has been approved by the Canadian regulator, Health Canada, in the treatment of Friedrich's attaxia, under the brand name Catena. It also is being developed in other orphan mitochondrial and neuromuscular diseases, including Duchenne's muscular dystrophy, where it is in Phase III.

The re-submission of Raxone in LHON will take 60 days to process, meaning a decision can be expected by the middle of 2013. Meier said the impact of the CHMP's initial rejection on Santhera as a whole is not clear as yet, but there will be a detailed update when the company reports financial figures in February.

Shares in Santhera (SWISS:SANN) fell by 20 percent on Friday morning to CHF3.80 when the news was announced.