BioWorld Today Correspondent

Amsterdam Molecular Therapeutics (AMT) N.V'.s bid to become the first Western biotechnology firm to gain a gene therapy approval suffered a second rebuff, as the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) stood over its original negative opinion on a marketing authorization application for Glybera (alipogene tiparvovec), which is in development for the ultra-rare indication lipoprotein lipase deficiency.

Shares in the company (AMSTERDAM:AMT) plunged 51 percent Friday, to close at €0.38 ($0.43).

AMT, of Amsterdam, the Netherlands, had sought a re-examination of the dossier following an initial negative opinion, which the CHMP handed down in June. (See BioWorld International, June 29, 2011.)

This time round, the CHMP has gone against the advice of its own Committee for Advanced Therapies (CAT), a multidisciplinary advisory body composed of European experts in gene therapy and cell therapy. The CHMP's own rapporteurs and an expert panel called the Scientific Advisory Group also backed approval of Glybera under exceptional circumstances, AMT said in a press release.

Its CEO, Jörn Aldag, was mystified at the outcome.

"We just don't understand what happened there," he told BioWorld Today. "The only explanation that we have received as a company is on two pages – in a question-and-answer document."

The CAT, which had initially opposed Glybera's approval as well, reversed its position during the re-examination process. It concluded that concerns about the lack of clinical evidence in support of Glybera's approval could be addressed with post-marketing studies, whereas the CHMP maintained that "the benefits of the medicine did not outweigh its risks due to questions over the medicine's benefits."

"I really did not expect this to happen, and I must say I'm disappointed with the communication we have received as to why it was rejected," Aldag said. "They're ignoring the advice they get from their rapporteurs and from the CAT."

At issue is the strength of the clinical evidence that AMT filed in its application. Lipoprotein lipase deficiency, which is caused by the absence of lipoprotein lipase, an enzyme responsible for breaking down triglycerides in lipoproteins, only affects about 350 people in Europe. AMT's pivotal trial recruited 27 patients, but the CHMP has ruled that it failed to show "sufficient evidence of a persistence of effect in lowering blood fats in a clinically relevant manner, and there were too few patients for whom sufficiently long-term data were available."

It also ruled that there was insufficient evidence to show that treatment with Glybera led to reductions in the rate of pancreatitis, the most serious side effect of the condition.

AMT has recruited 10 patients who have received Glybera into an observational extension study, which will examine the effect of the therapy on levels of lipoprotein particles called chylomicrons. Those who have received treatment will be compared with untreated patients and with healthy volunteers.

Data from this study are expected next March, but it is not yet clear whether AMT will have sufficient resources to continue the program, as it is running low on cash. (See BioWorld International, Aug. 31, 2011.)

The company will hold a conference call on Tuesday to set out its plans. It has a clinical-stage program in hemophilia B and preclinical efforts in Duchenne muscular dystrophy, acute intermittent porphyria, Parkinson's disease and Sanfilippo B.

AMT's gene therapy technology employs an adeno-associated viral vector. Its GMP process involves the use of a baculovirus expression system.

"The technology platform has not been criticized," Aldag said. "In all the communication we have from the EMA there does not seem to be any rejection of gene therapy as such."