Breakthrough for Europe as EMA gives the nod to the first gene therapy

After several false dawns, the vision of treating debilitating inherited disorders by administering a correct copy of a faulty or missing gene, is about to be realised, following the European Medicines Agency’s (EMA) recommendation that the first such gene therapy Glybera, should receive marketing approval.

This is a triumph for Glybera’s developer, uniQure BV, which has invested €50 million in the treatment for lipoprotein lipase deficiency, an ultra-rare inherited disease in which patients are unable to produce an enzyme that is needed to digest fat. But it also marks a tipping point for gene therapy as a whole, some forty years after it was first suggested that genes could be administered as medicines.

Of the €50 million uniQure has invested in Glybera, the regulatory process sucked up €15 million, an inordinate amount for a small biotech company. But those involved in the field believe this hard-won precedent sets out a path for products following behind, a number of which are now in the advanced stages of clinical development.

“I’m so pleased,” said Jörn Aldag, CEO of Amsterdam-based uniQure. “It’s been a long ride, but an important one, and the outcome is terrific because Glybera is something the EMA now permits us to bring to patients.”

Impossible regime

The most insidious consequence of lipoprotein lipase deficiency is the painful and recurrent attacks of pancreatitis that are sparked as undigested fat globules accumulate in the pancreas, causing inflammation. Before Glybera, the only recourse was a zero-fat diet, a regime it is practically impossible to maintain.

Certainly, a fat-free diet is at odds with pregnancy, and in a potent example of its transformative effects, a woman who was treated with Glybera in the clinical trials conducted by uniQure, increased her fat uptake and carried a baby to term, without suffering a single attack of pancreatitis.

This one case highlights how a decade of European Union policy-making aimed at building a framework in which national healthcare systems can work in concert to address rare diseases – many of which have an inherited component – is crystallised by the recommendation to approve Glybera.

It is also proof that efforts to create a pan-European system in which gene therapies and other novel treatments for rare diseases can be assessed by experts and regulated accordingly, are paying off.

One of the key reasons why the EMA deliberated so long over Glybera was that the small number of patients (only 27 were treated in the clinical trials) meant it was impossible to provide a conventional statistical demonstration of efficacy. Given that there were no concerns about the safety or the manufacturing, the decision to allow the product on the market and gather further evidence of efficacy afterwards, is another important way in which Glybera provides a role model for commercialising gene therapies for rare diseases, no matter how few patients there may be.

Major milestone

This is an “important juncture” for gene therapy believes Jason Loveridge, CEO of another gene therapy specialist, Genable Ltd . “We have reached a major milestone for our sector,” Loveridge said.

Genable is working to translate research carried out by scientists at Trinity College Dublin into retinitis pigmentosa, an inherited and progressive disease that causes severe vision impairment and blindness. With support from the patient group Fighting Blindness Ireland, the company anticipates starting clinical trials in 2014. Now that Glybera has been assessed and approved by the EMA these studies are “more likely” to be carried out in Europe, because the path for getting a gene therapy to patients, “is much clearer than ever before,” Loveridge said.

Ena Prosser, partner at Fountain Healthcare Partners, a venture capital fund that has put money into Genable, agrees about the significance of the Glybera decision. “This is important in terms of clarifying the regulatory route and will give investors more certainty.” She added, “I’m really glad Europe has made this advance; it will help innovation in Europe overall.”

Opening the door

The long, tortuous and high-risk process of developing gene therapies - and the setbacks along the way - has scared off all but the most stalwart investors and made for a hand-to-mouth existence for companies trying to commercialise these products.

One dedicated uniQure investor, Sander van Deventer, General Partner at the venture capital firm Forbion Capital Partners and a co-founder of uniQure, has kept the faith for over ten years. Now, he says, there will be a return on the energy, effort and hard cash that has gone into Glybera, and into gene therapy as a whole. “Things are going to change in gene therapy as a result of this decision; it opens the door to a new type of treatment.”

One demonstration the situation is changing came yesterday (25 July) when bluebird bio, a US gene therapy company in which Forbion is long-standing investor, announced that it had raised US$60 million in an oversubscribed fourth round of private funding. Adding to the sense that gene therapy is coming in from the cold, the Cambridge, Massachusetts-based company managed to attract five new venture capital investors.

Superior therapies

Glybera most obviously lights the way for other gene therapies for inherited disorders. But it also reads across to products that are administering genes to treat cancer, according to Nigel Parker, chairman of the gene therapy start-up, FKD Therapies OY of Kuopio, Finland. In addition to underlining it is safe to use certain viruses as vehicles for delivering genes, Glybera hints at the vastly superior therapeutic power of gene-based treatments, he said.

“Most gene therapies are under development for things that can’t be fixed with small molecule drugs: a big piece of biology has gone wrong and you need a big piece to fix it,” said Parker.

Gene therapy provides this fix by getting the body to make its own drug, in the right place and over time. FKD’s lead product Instiladrin, a treatment for bladder cancer, is a case in point. It uses an adenovirus to transport a gene for interferon, a well-established anti-cancer drug, into the cells in the wall of the bladder. This prompts the cells to generate interferon for around seven days following a single treatment, overcoming the fact that although it is highly potent, in bladder cancer the efficacy of interferon is limited because when injected directly, the drug is cleared from the bladder within 24 hours.

Changing treatment paradigms

Similarly, Stuart Naylor, chief scientific officer of UK gene therapy specialist Oxford BioMedica plc, says the example of Glybera highlights the potential of gene therapy to change the treatment paradigm in neurodegenerative diseases. The company’s lead product, ProSavin delivers genes for three different enzymes that are needed to generate dopamine, the neurotransmitter that is depleted in Parkinson’s disease.

While dopamine replacement is possible with L-Dopa, there are side effects, in particular uncontrollable movements, or dyskinesia, and in addition the drug becomes ineffective over time. The 15 patients treated with ProSavin to date (the product is injected into a precise region of the brain) have experienced a reduction in their symptoms and some have been able to cut back on the use of L-Dopa.

“A product like ProSavin is potentially a one-off treatment. It’s a completely different way of treating patients from repetitive dosing with L-Dopa,” Naylor noted.

High drama to farce

There is much cheer that Glybera is finally within sight of the finishing line. But there remains concern about the convoluted route that brought it to this point, with the regulatory process lurching from high drama to farce.

In January this year, the European Commission took the unprecedented step of refusing to rubber stamp EMA’s view that Glybera should not be approved following its second review, telling the Agency to take another look. These deliberations resulted in a 16 – 15 majority in favour of approving Glybera when the Committee for Medicinal Products for Human Use (CHMP) voted on the product for the third time in May.

Unfortunately, an absolute majority of all 32 members of the CHMP – or 17 votes - is needed for approval. On the day, one member was missing and Glybera got its third thumbs down.

At this point the EMA seems to have torn up its own rule book, because instead of referring the decision back to the European Commission, its decided to examine the file for a fourth time.

Ridiculous circle

As one of Europe’s leading advocates for patients with rare diseases, Alastair Kent says the approval of Glybera is “a triumph of common sense”. But he adds, “It’s a shame it had to go round in a ridiculous circle so many times.” Kent, Director of Genetic Alliance UK, a body which represents 150 rare diseases patients’ groups, suggests the EMA needs to look at its procedures and be sure it draws on the lessons of Glybera.

In its defence, Tomas Salmonson, acting chair of the CHMP said, “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.”

For now, the final word should go to Aldag, who is remarkably forgiving about the regulatory vicissitudes, saying, “In any revolutionary technology that’s completely novel and with no precedent, people have to learn, and the learning process is painful.” The fact that Glybera finally made it, “Is a reflection of the European Commission’s very clear agenda on innovation, and a desire to be delivering on that,” he said.