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European Commission Breaks With CHMP on AMT's Glybera

By Nuala Moran
Staff Writer

LONDON – There's been another twist in the gene therapy saga, with the European Commission refusing to give its usual rubber stamp to the European Medicines Agency's (EMA) decision not to grant marketing authorization to Glybera, a treatment for inherited disorder lipoprotein lipase deficiency (LPL).

That puts the regulator in Europe in uncharted territory, because it is the first time the European Commission's Standing Committee of the European Parliament has failed to agree with a recommendation from the EMA's Committee for Human Medicinal Products (CHMP) on whether to approve or reject a drug.

"It's never happened before that if [EMA] has issued a negative opinion, that the commission sent the file back," noted Jorn Aldag, CEO of Glybera's developer, Amsterdam Molecular Therapeutics NV (AMT). The rebuff throws a possible lifeline to AMT, which was forced by the CHMP's rejection to lay off half its workforce and halt development of Glybera (alipogene tiparvovec). (See BioWorld International, Oct. 26, 2011.)

The Standing Committee, composed of elected members of the European Parliament representing countries across Europe, failed to reach an agreement and has requested additional information from the CHMP. AMT wrote to all Standing Committee members before their meeting last week to contest the CHMP's recommendation that Glybera be refused marketing authorization, saying the CHMP "[had] not fully considered the critical evidence."

The letter, signed by Aldag, called on the Standing Committee not to ratify the opinion of the CHMP, but to send Glybera back for reconsideration, saying all those concerned would benefit: "Patients could be treated with the only potentially available treatment option, the applicant [AMT] could avoid further financial disaster, the advanced medicinal therapy industry would get a signal for further innovation and regulatory clarity and [EMA] would overcome what is currently perceived as a severe transparency issue."

"We are now in new territory, and I'm not sure whether the process is clear from here," Aldag told BioWorld International.

AMT has asked for further information but has not yet heard what the timeline is for the CHMP to respond to the Standing Committee's rebuff. The EMA did not respond to BioWorld International's request for a comment on the situation.

There is no treatment for LPL, an ultra-orphan disease which causes recurrent pancreatitis. The sticking point for the CHMP is not related to any aspect of Glybera as a gene therapy. Rather, the committee questioned whether clinical studies of Glybera have demonstrated that delivering correct copies of the LPL gene has a clinical impact, enabling patients to break down fat particles called chylomicrons that circulate in the blood after eating. The particles can accumulate resulting in severe acute inflammation of the pancreas.

Although only 27 patients in total have been treated, AMT claims the CHMP is at odds with other experts on the question of clinical benefit. In particular, the Committee for Advanced Therapies, set up to give scientific advice on gene and cell therapies, recommended Glybera be approved. Given there are no safety concerns, AMT says approval should be granted with the proviso that patients who have received the one-off gene therapy treatment continue to be followed.

In the letter to the Standing Committee members Aldag claims the CHMP has not followed the EU's rules for approving orphan drugs, which says that if controlled trials leading to statistical significance cannot be conducted, individual (narrative) patient data should be weighed in assessing possible benefit.

The company has undertaken to maintain a patient registry and has agreed to a risk management plan under which no more than two patients per month would be treated, at a limited number of expert centers.

Amsterdam, the Netherlands-based AMT received the non-approvable opinion from the CHMP in October 2011 , after requesting a re-examination of the dossier, which was first rejected by the CHMP in June 2011.

Last month the venture capital investors in AMT put $3.2 million into the company in the hope that would enable it to stay solvent long enough to close a deal for its gene therapy treatment for hemophilia B. The treatment, which has U.S. and EU orphan drug status, is the first gene therapy to reduce bleeding episodes, as demonstrated in a clinical trial involving six patients. (See BioWorld International, Jan. 4, 2012.)