First Gene Therapy Glybera (Finally) Gets EMA Approval
By Nuala Moran
LONDON – The first gene therapy to be approved in a Western regulated market finally made it over the finishing line on Thursday when the European Medicines Agency (EMA) gave the nod to Glybera after considering the treatment for lipoprotein lipase deficiency (LPL) for the fourth time.
The developer, uniQure BV, is now looking at filing for FDA approval on the basis of the same clinical data that eventually convinced the EMA. "I'm pretty certain [the FDA] will accept it," CEO Jörn Aldag told BioWorld International.
"I'm happy," he added. "We can tell people we're number one; we've done it. Glybera is approved, and gene therapy is something that the EMA now permits us to bring to patients."
The historic approval is not only a breakthrough for gene therapy, but it also heralds a significant advance in the EMA's views of how clinical benefit should be assessed in rare diseases with high unmet medical need, where there are not enough patients to deliver statistically significant trial results. The much-studied file for Glybera (alipogene tiparovec) holds details of 27 patients only.
The drawn-out process of approving Glybera has led the EMA into uncharted waters. In January, the European Commission refused to give its usual rubber stamp when the EMA recommended for the second time that Glybera be rejected, taking the unprecedented action of telling the agency to think again. Then, when its Committee for Medicinal Products for Human use (CHMP) vetoed Glybera for the third time in April, the EMA did not refer the negative verdict to the European Commission for approval, but took an internal decision to send Glybera back to the CHMP once more.
The news is a triumph for uniQure (formerly Amsterdam Molecular Therapeutics), which has invested €50 million (US$60.8 million) in developing Glybera, of which it was forced to lavish €15 million on the protracted regulatory process. The impact of that was such that just before the EMA turned down Glybera for the third time in May, Amsterdam Molecular Therapeutics was de-listed, with the gene therapy assets being signed over to privately held uniQure. (See BioWorld Today, April 23, 2012.)
Alastair Kent, director of Genetic Alliance UK, which represents more than 150 patient groups, said, "The decision the CHMP has finally made is the right one and a significant one. Gene therapy is not a panacea, but it does have the potential to address very significant unmet needs."
But he told BioWorld International, "It's a shame Glybera had to go round in this ridiculous circle so many times; the EMA needs to look at its procedures."
Putting the glory to one side, with pricing and reimbursement and marketing strategy still to be decided, the commercial significance for uniQure of the approval of Glybera is not clear at this point. "It's too early to talk about the commercial implications," Aldag said. "We don't know about pricing or the number of patients, though we estimate there are between 1 ,000 to 5,000 worldwide."
UniQure ended work on Glybera when the EMA turned it down for the second time in October 2011. "We stopped all work and abandoned all the structures. We will now go ahead and rebuild," Aldag said. "There are two possible roads: one a partnership, the other doing it ourselves."
The EMA is recommending approval of Glybera as a treatment for LPL under exceptional circumstances, meaning it will be administered at a few specialist centers. "We might need three clinics in Germany, two in Holland, for example, and so it will take a limited number of people to bring [Glybera] to patients," Aldag said.
Patients with LPL are unable to process fat particles in the bloodstream, which accumulate to cause severe attacks of pancreatitis. "Patients with LPL are afraid of eating a normal meal because it can lead to acute and extremely painful inflammation of the pancreas, often resulting in a visit to intensive care," Aldag noted. "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 multiyear beneficial effect after just a single injection."
The need for a single treatment marks a divide between Glybera and enzyme replacement therapies for similar inherited enzyme deficiency disorders, which must be administered on a chronic basis. Marketed enzyme replacement therapies cost between €150,000 and €450,000 per patient, per annum, and Aldag thinks the pricing for Glybera should be a multiple of some price in that range to reflect the fact that a one off-treatment with Glybera has an effect that lasts over years.
For Aldag, one of the most frustrating aspects of the regulatory delay was that neither the CHMP nor its expert advisory group, the Committee for Advanced Therapies (CAT), had any safety concerns about Glybera's use of an adeno-associated virus vector to deliver working copies of the LPL gene into muscle cells to enable production of the enzyme in the cells.
"If the CAT had been dubious [about safety] I wouldn't have done anything, but with the CAT clearly positive it had to be pursued. Sometimes you just get the feeling something is wrong, and you need to do something," Aldag said.
The CHMP's recommendation that Glybera be approved under exceptional circumstances means uniQure will be required to set up a registry to monitor outcomes in patients treated with Glybera, which the EMA will review.
In its defense, Tomas Salmonson, acting chair of the CHMP, said the established ways of assessing the benefits and the risks of Glybera were undermined 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."
Christian Schneider, chair of the CAT, said he was concerned about reports of differences between the two committees during the approval process, noting, "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."