A GENE THERAPY-BASED PRODUCT APPROVED AT LAST
The first gene therapy trials date from the late 1980s. In the intervening years, more than 1800 such trials have been approved/initiated
world wide. Until 2012, no gene therapy-based product had gained approval for human use in the western world, although a small
number of such products have been approved in China (5) and four gene therapy-based drugs/vaccines have been approved for
veterinary use in the West (6).
A significant milestone for gene therapy was achieved on Oct. 25, 2012, with the approval of Glybera (alipogene tiparvovec)
by the European Commission for use in the treatment of lipoprotein lipase deficiency within the EU. Lipoprotein lipase (LPL)
deficiency is a rare genetic condition, affecting 1 in 500,000 individuals and, therefore, the approved product has orphan
status. The condition is characterized by absence/near absence of lipoprotein lipase, an enzyme central to dietary-derived
lipid metabolism and distribution in the body. The enzyme is expressed primarily by muscle cells and adipocytes and is central
to the processing of circulating triglyceride-rich lipoproteins.
Glybera is a replication-deficient adeno-associated viral vector housing a human lipoprotein lipase gene. The product is administered
intramuscularly, and the resultant transduction of the surrounding muscle cells results in functional LPL expression, leading
to an anticipated positive therapeutic outcome. The vector genome persists in the nucleus of transduced cells as episomes,
leading to long-term expression of the transgene. It is anticipated that treatment will be a once-off series of intramuscular
injections into the legs. Treatment will certainly not be inexpensive, with as estimated cost in the region of $1.6 million
(€1.2 million) per patient.
Despite its eventual approval, European Medicines Agency (EMA) evaluators had some reservations about the product. The Committee
for medicinal products for human use (CHMP) considered the Glybera application—and adopted a negative opinion—on two previous
occasions in 2011 (7). The committee appeared initially to have a number of product quality-related and efficacy-related concerns,
and final product approval is restricted to a subset of LPL-deficient patients suffering the most serious condition-related
effect, that of severe or multiple pancreatitis attacks.
The approval of Elelyso (taliglucerase alfa) by FDA in May 2012 represents another technological milestone, in that it is
the first product approved for human use that is produced using a plant-based expression vector. Glycoprotein production in
plant-based systems generally results in the formation of hyperglycosylated product containing various sugar moieties immunogenic
in man. The sugar chains are devoid of sialic acid caps, which can negatively influence their serum half-life.
Elelyso is a recombinant human glucocerebrosidase used as a replacement therapy to treat Gaucher disease, a rare lysosomal
storage disorder. The recombinant protein displays terminal mannose residues in its glycocomponent, facilitating direct product
uptake by macrophages (the target cell type) via cell surface mannose receptors.
Interestingly, a parallel marketing authorization application for Elelyso submitted to the EMA was refused. However, the grounds
for European refusal was not scientific in nature, but was due to the existence of a 10-year marketing exclusivity granted
to a substantially similar product (trade name Vpriv), approved by the European Commission in August 2010.