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Glybera Misses Majority Vote; Gets Third CHMP Rejection

By Nuala Moran
Staff Writer

LONDON – The gene therapy Glybera has been rejected for the third time, despite the fact that the European Medicines Agency's (EMA) Committee for Medicinal Products for Human use (CHMP) last week voted 16 to 15 in favor of approving the treatment for ultrarare inherited disorder lipoprotein lipase deficiency (LPL).

Unfortunately, for a product to get the nod, it needs an absolute majority – or 17 votes – from all the members of the 32-strong committee, not just members who are present to vote. CHMP members who are not present cannot vote in absentia.

An evidently bemused and disappointed Jörn Aldag, CEO of Amsterdam Molecular Therapeutics BV (AMT), Glybera's developer, described the arbitrary turn of events as "amazing," telling BioWorld International, "I don't think there's any more we can do; we've made the case well known, but now the process is at an end."

Last month AMT was taken private, transferring its gene therapy assets to a new company, uniQure BV, and Aldag said there will be no further investment in Glybera (alipogene tiparvovec).

Alastair Kent, one of Europe's leading advocates for people with inherited genetic disorders, told BioWorld International it is a case of "bureaucracy gone bonkers." The CHMP is not only flying in the face of the policy of the European Commission, it also is acting against the express wishes of the European Parliament and the impetus that the European Union's health directorate DG Sanco is putting behind the development of new treatments for rare diseases.

It remains to be seen if the European Commission will now back the CHMP's opinion, having refused in January to give the usual rubber stamp to the committee's recommendation to reject Glybera, and telling it to think again.

Kent, director of Genetic Alliance UK, a body representing more than 150 patient groups, said, "I hope the Commission exercises its prerogative and re-refers Glybera back to the CHMP."

The CHMP's decision is contrary to earlier positive advice from the EMA's Committee for Advanced Therapies (CAT), which was set up specifically to provide expert guidance to the CHMP on advanced therapeutics such as gene and cell therapies. Adding further weight to the case for Glybera, the EMA's Scientific Advisory Group (SAG), an expert panel specifically selected to evaluate clinical results and the science underpinning a product, also recommended that it should be approved under exceptional circumstances. Kent – a former member of CAT – said it is "a fault in the drafting of the rules" that CHMP should be able to disregard the recommendations of CAT and SAG, two committees with more relevant and specific expertise than the CHMP.

AMT's Aldag criticized the "intransparent process" by which the CHMP reached its decision, despite CAT and SAG recommending approval. "The rules need to be clear because otherwise in the future people just won't make the investment," he said.

The CHMP did not reject Glybera on safety grounds, but because it said there is not enough proof the one-off treatment is effective in controlling the acute attacks of pancreatitis that are the hallmark of LPL. According to the CHMP, "The reduced risk of pancreatitis seen in a few of the patients could have been due to other factors, such as changes in lifestyle and diet, and the natural course of the disease."

As Aldag pointed out, patients have indeed changed their diets and lifestyles, since without treatment the only way to avoid attacks of pancreatitis is to maintain a zero-fat diet. "After treatment, some patients had a significant increase in body weight because they were able to eat more fat, but with reduced incidence of pancreatitis," he said.

While it is obviously impossible to provide statistically significant data in orphan diseases, Aldag contended there is enough evidence to grant approval of Glybera under exceptional circumstances. AMT had undertaken to maintain a patient registry and to put in place a risk management plan under which no more than two patients per month would be treated, at a limited number of expert centers.

Kent agreed that approval should be given under exceptional circumstances, allowing any questions to be addressed by postmarketing surveillance.

He said he believes the case could set an awkward precedent for orphan diseases as a whole. "Frankly, it's discriminatory to those affected by rare diseases to set the evidence bar at an impossible height and demand standards of proof it is impossible to provide," he said.

There also are potential implications for the development of personalized medicines, Kent argued. "When you put common diseases into subsets, you can't go down the traditional, controlled trials approvals route. This is pulling the rug out from under researchers, pharmaceutical companies and investors in personalized medicine."