Human Gene Therapy Gets the Nod

The Lancet, Volume 380, Issue 9855, Page e10, 17 November 2012
doi:10.1016/S0140-6736(12)61992-8Cite or Link Using DOI
Europe officially approved its first gene therapy earlier this month for a rare metabolic disorder. Could this mark a turning point for a technique that has struggled to take off? Karl Gruber reports.
On Nov 2, the European Commission announced the official approval of Glybera, a gene therapy for treating lipoprotein lipase deficiency (LPLD), devised by the Dutch company uniQure. The approval is the first of its kind in the Western world and may herald the beginning of a new era for gene therapy, a field plagued by unfulfilled promises and weary investors, all of which has until now overshadowed its progress.
LPLD is an extremely rare and incurable disorder that affects 1—2 people per million, where a defective lipoprotein lipase (LPL) gene leads to a non-functional LPL enzyme. The LPL enzyme is a key player in fat metabolism and people with LPLD are unable to process fats. They suffer from severe abdominal pain during childhood and several other conditions during adulthood, including recurrent acute pancreatitis
Glybera (alipogene tiparvovec) is a recombinant, non-integrating, non-replicating adeno-associated viral vector expressing Ser447X, a naturally occurring functional variant of the LPL gene associated with lower rates of cardiovascular disease and increased efficiency in fat metabolism. The basic principle of Glybera is to compensate for the defective LPL gene by introducing functional copies of this gene into muscle cells lacking active LPL. Patients receive a single treatment that, according to clinical data, results in long-term improvement of the conditions associated with LPLD, including a reduction in pancreatitis incidence up to 2 years after treatment.
The road to Glybera's approval was not simple, being hurdled by three rejections before success. The first two rejections, back when uniQure was Amsterdam Molecular Therapeutics, were due to the low number of patients studied. The third rejection happened by a very tight vote (16 to 15) and one absentee that tipped the balance against them. However, the safety of the treatment was never in question, the European Medicine Agency acknowledged that Glybera met all safety standards.
A spokesperson for uniQure tells The Lancet that the big problem was to answer the question: is it effective? “We said yes, but the Agency was not certain.” Part of the difficulty was establishing statistically significant efficacy with the low number of patients studied. “With 1000s of patients that are treated in clinical trials for large indications that is much more straightforward; but with 27, it becomes a very different equation. And regulators need to come to terms with that when faced with orphan drugs.” It seems “good will” came after the fourth application, with a request that uniQure keeps a record following up the wellbeing of their patients.