A gene therapy medicine has been recommended for authorization in the European Union for the first time. Glybera (alipogene tiparvovec), developed by uniQure, a Dutch biotech, is designed for patients with the genetic disorder lipoprotein lipase deficiency (LPLD) who have severe or multiple pancreatitis attacks, despite dietary fat restriction. The medicine is administered as a single injection.

The European Medicine’s Agency announced on Friday that its Committee for Medicinal Products for Human Use (CHMP) has recommended Glybera be authorized for marketing in the European Union. The authorization would cover all 27 EU states.

The CHMP has recommended that Glybera be put forward for marketing authorization, but under “exceptional circumstances”, whereby uniQure will be required to carry out post-marketing surveillance. They will have to set up a registry to monitor outcomes in patients receiving the treatment, and the Agency will review the data as it becomes available.

The final decision rests with the European Commission, who usually follow CHMP’s advice. UniQure said they expect this to happen within the next three months.

LPLD is a rare disease and there is no current treatment. It affects about one or two people per million. It is caused by a mutation in the LP gene, resulting in much diminished or absent activity of LPL proteins. LPL proteins are enzymes that break down chylomicrons, large fat-carrying particles that end up in the blood after food digestion.

If they aren’t broken down, chylomicrons collect in the blood and can block small blood vessels. This can lead to recurrent and severe acute inflammation of the pancreas (pancreatitis).

Currently, the only way to help patients with LPLD is to put them on a strict fat-reduction diet that limits their fat intake to no more than 20% of their daily calories. It is not easy to stick to such a diet, and consequently many patients end up in hospital with life-threatening pancreatitis attacks.

Gene therapies work by replacing defective genes in the patient’s DNA with working genes. Glybera uses an adeno-associated virus to insert working copies of the LPL gene into muscle cells so they can produce the enzyme in normal quantities.

Because LPLD is such a rare condition, the EC granted Glybera orphan medicine status in 2004.

Applications to authorize marketing of orphan medicines are usually fast-tracked, and the companies that develop them usually receive financial incentives, such as tax incentives and more time to recoup their investment before the drug is open to the competition. In the US, such market exclusivity lasts for 7 years, in the EU it lasts for 10 years.

However, the evaluation of Glybera’s application has not been straightforward.

The first application was made in 2009. In June 2011, both the CHMP and the Committee for Advanced Therapies (CAT), which was brought in to carry out additional analyses, said they were not in favour, according to an EMA press release, they “adopted negative opinions concerning the use of Glybera in the treatment of patients with LPL deficiency”.

Then there was a re-examination, where the CAT said perhaps there was scope to give Glybera approval, as long as there were additional post-marketing studies, but the CHMP stuck by its negative opinion until October 2011.

But following a meeting of the Member States Standing Committee on human medicinal products in January 2012, the EC asked the EMA to re-evaluate Glybera’s application by focusing in a restricted group of patients with severe or multiple panacreatitis attacks.

There ensued detailed scientific discussions in both the CHMP and the CAT, after which the CAT changed its position and “adopted a positive draft opinion in June 2012”, which the CHMP has subsequently endorsed.

Dr Tomas Salmonson, acting Chair of the CHMP, explained that the CHMP now concludes, from evaluating the data for the restricted group of patients, the benefits of Glybera outweigh the known risks.

“Our established ways of assessing the benefits and risks of Glybera were challenged by the extreme rarity of the condition and also by uncertainties associated with data provided. In close cooperation with the CAT we have worked out a way to ensure robust and close follow-up of the quality, safety and efficacy of Glybera while giving patients who have to live with this rare disease access to a medical treatment,” said Salmonson.

Dr Christian Schneider, the Chair of the CAT, said the two committees worked closely throughout the procedure.

“I was concerned about reports in the public domain of differences between the two committees during the approval process, since the scientific assessment of the CAT and the CHMP were not far apart. The dossier is maybe a unique case where the ultra-rarity of the disease, its fluctuating rather than continuously progressing clinical course, and the complexity of the scientific data led to difficult scientific decision-making,” he explained.

Jörn Aldag, CEO of uniQure, said the CHMP’s positive recommendation is a major breakthrough for LPLD patients and for medicine.

“Glybera is poised to become the first in a class of gene therapy products approved in Europe to treat orphan diseases, rare conditions with a very high unmet medical need,” he added.

He said patients with LPLD are afraid to have a normal meal because of the possibility that afterwards they will suffer acute pain from pancreatitis, which can also mean a visit to intensive care.

Now, for the first time, a treatment exists for these patients that not only reduces this risk of getting severely sick, but also has a multi-year beneficial effect after just a single injection,” said Aldag.

Giving these patients’ bodies the ability to break down fat particles naturally in the blood, without leading to the excruciating pain of pancreatitis is “what gene therapy is all about: curing disease at the genetic level,” he added.

Written by Catharine Paddock PhD