The second and final European rejection of gene therapy Glybera last week came as a big disappointment for those awaiting the first regulatory breakthrough for this high risk sector of drug development. For Amsterdam Molecular Therapeutics, which has been striving for almost two years to win a marketing license for the therapy, the decision is a damaging blow.
Announcing a painful restructuring this morning, AMT’s chief executive Jörn Aldag said the company was “shocked” to receive the final verdict after three separate groups of advisors, which report to the Committee for Medicinal Products for Human Use, had backed the product. The CHMP has yet to explain its contrary stance, prompting the company to lambast a lack of transparency in the process – rather than simply moving the goalposts AMT complains it has never been told where to aim.
By one voice
Despite an initial rejection this summer by both the CHMP and its Committee for Advanced Therapies (CAT), the regulator encouraged the company to appeal the decision in the hope that various queries and concerns could be allayed (AMT's gene therapy rebuffed as cash clock ticks, June 24, 2011). A treatment for a very rare genetic condition called lipoprotein lipase deficiency (LPLD), Glybera replaces a gene lacked by sufferers that codes for a crucial enzyme needed to break down fat in the bloodstream - administration involves a one-off series of 40 intramuscular injections over three hours. The gradual accumulation of fat in the blood causes the potentially fatal complications of LPLD: pancreatitis and cardiovascular problems.
Two new CHMP rapporteurs were appointed to guide the appeal, as well as an external scientific advisory group consisting of European experts in the areas of gene therapy, lipid metabolism and pancreatitis, to review and analyze the data and advise the regulators.
The scientific group concluded that Glybera should be approved under exceptional circumstances, a verdict backed by the rapporteurs and ultimately the CAT, which shifted its opinion and this time voted by a large majority in favour of allowing Glybera on the market, AMT says.
This failed to sway the CHMP, which voted by a very narrow margin to block marketing authorisation – coming down to “one voice on the CHMP”, Mr Aldag said on a conference call this morning.
Although the CHMP must lay out the reasons for its differing opinion to the CAT, this has not yet been received by the company. The committee has only said they consider Glybera to be potentially valuable but that the benefits did not outweigh the risks. What these perceived risks are remain to be clarified although AMT suspects it concerns the use of immunosuppressants and the long term impact of the intramuscular injections through which Glybera is administered.
LPLD only afflicts one or two people in a million – an ultra orphan indication that probably did not help Glybera’s case. Only 27 patients have ever been treated with the therapy – a figure the regulator said they had no problem with. But as well as establishing safety AMT had to persuade the EMA its techniques for measuring Glybera’s impact on patients’ lives were relevant. A big challenge for a little-studied disease, and a change in primary endpoint mid way through development could have made regulators uneasy.
At the end of the day, the company failed to mount a convincing argument that Glybera yields longer term benefits for patients – whether that was entirely down to the regulator’s failure to communicate what it wanted to see is hard to say. But for now in Europe, Glybera has hit a wall.
“The company will not pour your money into further development of a drug where the [regulatory] process is not transparent and clear,” Mr Aldag told investors today.
Talks will be held with regulators in the US and Canada to see if filings can be made on existing data; a requirement for further trials from either of these parties will likely put the project to bed for good.
Half of the company’s 90-strong workforce will lose their jobs and partners found for other projects – a haemophilia B candidate in particular is looking promising, according to the company – with existing funds, some anticipated support from existing shareholders and significantly reduced cash burn the company could limp on for a couple more years.
The only silver lining – regulators did not have a problem with approving a gene therapy per se – just Glybera. For those considering following AMT on this tortuous regulatory path, that will provide little comfort.