Amsterdam Molecular Therapeutics BV's potential gene therapy, Glybera (alipogene tiparvovec), may have been rejected for approval by Europe's top scientific advisory panel, CHMP, on Oct. 21, but the closeness of the vote - there was only one dissenting voice - suggests it won't be long before a gene therapy product clears the committee and reaches the European market.

But that product is not expected to be Glybera, because its development is being terminated by AMT. The company says it has come to the end of CHMP's appeal procedure, and a refiling would be too expensive.

AMT also is slashing its workforce from 88 to around 50 employees, and halving the size of the facilities it occupies in Amsterdam. "We have no more money to invest in a non-transparent process, and we have no idea how to gain European approval for Glybera," AMT's CEO Jorn Aldag told analysts on a call on Oct. 25. Since it was set up in 1998, around €100 million has been invested in AMT.

There is a glimmer of hope for Glybera from the U.S. and Canada, however. AMT is to hold meetings with FDA and the Canadian regulatory authorities in mid-November, when it will ask their views on Glybera and gene therapy. If the regulatory agencies are positive about the drug, then project funding could be sought to support filing of marketing authorizations in North America in the second half of 2012, Aldag said.

AMT is the second company in the past two years to see a potential gene therapy fall at the last hurdle in Europe - Ark Therapeutics Group PLC's gene therapy for malignant glioma, Cerepro, was rejected by CHMP in December 2009. But gene therapy experts believe European regulators are not opposed generally to the concept of gene therapy, and in certain aspects the recent news is promising for the sector.

"Although the rejection is terribly disappointing for AMT, the company's work represents a step forward for the whole industry, with two expert subcommittees in effect saying that now is the time to approve a gene therapy," one expert told "The Pink Sheet" DAILY. AMT pointed out that CHMP did not identify any safety risks with its adeno-associated virus-vector technology, which will allow it to be used as a platform technology.

Shocked By The Rejection

Aldag said CHMP's decision to reject Glybera came as a shock, as the company thought it had followed the guidance from regulators. He has been unable to get an explanation from CHMP about why its decision differs from that of two expert subcommittees, which cleared the product for approval.

Glybera first was rejected by the CHMP in June 2011, a decision which the company appealed (Also see "CHMP Positive On Trajenta, Vectibix, Votubia And Eurartesim, But Negative On Bronchitol, Luveniq And Glybera" - Pink Sheet, 27 June, 2011.). New rapporteurs from Italy and Latvia were appointed, and they concluded that Glybera should be approved under exceptional circumstances, if certain post-approval commitments were made by AMT.

An ultra-orphan drug like Glybera can be approved under the EU's exceptional circumstances provisions if it's unlikely that sufficient patients can be studied to prove a statistically significant benefit in a clinical trial, Aldag explained. Glybera's clinical benefit was being evaluated in patients with pancreatitis caused by a genetic defect, lipoprotein lipase deficiency.

A Scientific Advisory Group, a panel of independent experts set up by the European Medicines Agency to review the evidence, came to a positive conclusion on the drug, as did the EU's Committee on Advanced Therapies, both of which reviewed the findings of the Italian and Latvian rapporteurs.

However, in its Oct. 21 decision, CHMP again rejected Glybera for approval, saying its benefits did not outweigh its risks, primarily because of questions about its clinical benefit. In its June discussion, CHMP had argued that there was insufficient evidence that Glybera's effects on lipid levels persisted, or that it reduced the rate of pancreatitis.

Cash Burn To Be Slashed

The headcount reduction at AMT will bring the company's cash burn down to about €0.5 million to €0.6 million a month from €1.5 million per month, and along with a potential €10 million cash injection which is being discussed with existing and new shareholders, could extend the company's runway by almost two years.

The company says it intends to focus on collaborating with academic groups that have access to grants and other forms of non-dilutive funding, and will be seeking industry partners to work with it on these programs.

Aldag highlighted progress with its hemophilia B gene therapy program, in which several patients have been able to stop prophylactic injections following treatment with the gene, and its promising academia-partnered programs in glial cell derived neurotrophic factor and acute intermittent porphyria. Its collaboration with Institut Pasteur on a Sanfilippo B gene therapy will also continue. However, its Duchenne muscular dystrophy research program has been halted because it was consuming most of AMT's research budget.

- John Davis (j.davis@elsevier.com)

Amsterdam Molecular Therapeutics Ends Glybera Development, Halves Workforce

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