The EMA in London gives a thumbs down to AMT's gene therapy in May. Credit: EMA

For the third time, the European Medicines Agency (EMA) recommended that Glybera, a treatment for the inherited disorder lipoprotein lipase deficiency (LPL), should not be approved. The refusal on April 20 means there's still no approved gene therapy in a regulated Western market. It was bad news for suffers of the ultra-rare disorder and amplified the fault lines that the review of the product has opened up, both between different expert committees of the EMA, and between the agency and its masters at the European Commission.

Indeed, EMA's Committee for Medicinal Products for Human Use (CHMP) only got to vote on the product for a third time because in January the commission refused to rubber stamp an earlier recommendation to reject Glybera (alipogene tiparvovec), taking the unprecedented step of telling the CHMP to think again.

Glybera was not turned down because of any concerns about the safety of using an adeno-associated viral vector to deliver a correct copy of the aberrant gene, but because the CHMP concluded the developer, Amsterdam Molecular Therapeutics (AMT), had not demonstrated Glybera's efficacy in reducing attacks of acute pancreatitis that are the hallmark of LPL. The decision to reject Glybera could not have been closer. An absolute majority of the 32-member-strong committee—17 votes—was needed for approval. But on the day the CHMP voted 16-15 in favor one member was absent, and Glybera got the thumbs down.

Not only was the CHMP's decision to reject Glybera balanced on a knife edge, it was also contrary to advice received from the EMA's Committee for Advanced Therapies (CAT), a body set up specifically to provide guidance to the CHMP on gene, cell and tissue therapies. After convening an expert group to evaluate the clinical data and the science underpinning the product, CAT recommended Glybera should be approved under exceptional circumstances that would strictly limit the situations in which the one-off treatment is used, but allow efficacy data to accumulate.

Anyone with any common sense can see the drug is fit to be approved,” said Jörn Aldag, CEO of AMT. That it hasn't been is “purely bureaucratic,” he claims. AMT, of Amsterdam, has now been taken private, transferring its gene therapy assets to a new company, uniQure BV, and there will be no further investment in Glybera.

Alastair Kent, one of Europe's leading representatives of rare diseases patients' groups, agrees the decision is “perverse” and says the CHMP “should not be allowed” to ignore the advice of CAT, which is the committee “best qualified” to judge the quality, safety and efficacy of advanced therapies.

Kent, who is head of Genetic Alliance UK and president of the European Genetic Alliances' Network, has written to the European Commission to protest the decision.”

In the case of Glybera, the CHMP was weighing data from only 12 patients when it concluded the reduced incidence of pancreatitis could have been due to other factors “such as changes in lifestyle and diet, and the natural course of the disease.”

As Aldag notes, patients have indeed changed their diets because without treatment the only way to avoid acute pancreatitis is to maintain a zero-fat diet. He believes that with so few patients affected by such an insidious disease, individual case histories should be allowed to count. For example, although a fat-free diet is obviously at odds with pregnancy, one woman treated with Glybera increased her fat intake and carried a baby to term without suffering a single attack of pancreatitis.

For Kent, the decision to reject Glybera is not only bad in itself, it is likely also to have important consequences for the development of therapies for rare diseases. The regulatory process alone cost AMT €15 ($19) million of a €50 ($63) million total investment in Glybera. “The difficulties in generating evidence to support approval of treatments for very rare conditions are well demonstrated. If the CHMP insists on setting the bar unreasonably high, investors won't take the risk,” Kent says.

The European Commission has until mid-June to respond to the recommendation that Glybera be rejected. Having refused to agree once, it remains to be seen if it will now back the CHMP's opinion.