January 1, 2013 (Vol. 33, No. 1)

James M. Wilson, M.D., Ph.D.

Road to EU Approval Was Paved with Ups and Downs, But the Future Looks Bright

Glybera (alipogene tiparvovec) made history on November 2 when the European Union approved its marketing application, making the gene therapy the first to win approval by Western regulators.

In many ways, the story of Glybera is the story of AAV and gene therapy itself.

The story begins in the 1960s, when six different AAVs were identified based on the discovery that preparations of adenoviruses came from people and monkeys. Some of those preparations were contaminated with something that, under a microscope, looked like a virus. Not knowing where the contaminant originated, researchers began calling it adeno-associated virus, or AAV.

We knew the six different AAVs were probably structurally distinct, because antibodies to one did not cross-react with antibodies to the others. We also thought that some were infectious agents in humans, because some humans had antibodies circulating in their blood that reacted to these AAVs. One of them, AAV2, was sequenced in the 1980s and became an attractive vector for in vivo gene therapy because it was stable and didn’t cause much immune reaction.

A number of companies tried to demonstrate that AAV2 could be used successfully in patients. Avigen tried AAV2 for hemophilia, using a muscular or intravenous administration. It failed because there was little expression, and some immune toxicity. Targeted Genetics evaluated AAV2 for cystic fibrosis, only to fail because there was no evidence for gene transfer. Later, the company injected the vector into the joint, hoping to treat a form of arthritis. That didn’t work.

About three years ago, three academic groups showed that AAV2 can correct a rare form of inherited blindness, by targeting a certain cell type within the retina. Except for that disease, AAV2 fell short on all fronts.

Around that time, I was involved in a startup biotech company called Genovo. We appreciated the limitations of AAV2, so we focused on developing a vector based on AAV1. The hope was that since AAV1 was different than AAV2, it may be better in terms of less immune toxicity and more efficient gene transfer. AAV2 is very inefficient for important targets, such as the liver, heart, muscle, and lung.

We developed AAV1 as a vector, published a paper, and the University of Pennsylvania filed a patent and licensed it to Genovo, which soon thereafter was acquired by Targeted Genetics. Upon acquiring the AAV1 rights, Targeted Genetics sublicensed the vector for applications for congestive heart failure to Celladon and to Amsterdam Molecular Therapeutics (AMT, now uniQure), for patients with lipoprotein lipase deficiency (LPLD, or familial hyperchylomicronemia).

AMT selected a reasonable disease to go after. Patients with LPLD have very high levels of triglycerides in their blood, which can be toxic enough to the pancreas to cause severe pancreatitis. I also think it was a good disease because there was a biomarker for assessing the gene transfer, serum triglycerides.

AMT also raised a lot of money, so when the field lost favor with investors, and first-generation companies either were acquired or ran into trouble, this second-generation company was able to sustain itself. There was an unmet need for this disease and a good biomarker for gene transfer, so AMT proceeded with a clinical trial.

AMT’s problem was that LPLD is an extremely rare disease, affecting only a few hundred patients in the U.S. and Europe. From a commercial standpoint, that isn’t necessarily very attractive. AMT performed a Phase I safety study escalating the dose of vector and subsequently a small Phase II/III trial, with the primary endpoint a sustained decrease in triglycerides.

The vector did appear to decrease triglycerides, however, in most cases the triglycerides drifted back to pretreatment levels, causing AMT to fail in its primary endpoint. Instead of a placebo control, which is hard to do ethically and practically with rare-disease drugs and gene therapy, the company followed its subjects before giving the vector, then measured their serum triglyceride and catalogued their frequency of pancreatitis, the study’s secondary endpoint.

AMT saw that the frequency of pancreatitis was diminished after gene therapy, and submitted a dossier for approval to the EU’s European Medicines Agency, followed by a third study, including a metabolic analysis measuring the rate of degradation in the blood of chylomicrons, which harbor most triglycerides, before and after gene therapy. While the study has yet to be published, the company has reported a significant increase in chylomicron turnover.

Notwithstanding those results, AMT saw more than a year of negative recommendations from EMA’s Committee for Medicinal Products for Human Use (CHMP) against Glybera on risk/benefit grounds, despite positive opinions by EMA’s Scientific Advisory Group and Committee for Advanced Therapies, which concluded any concerns could be addressed by postmarketing studies. Getting Glybera successfully through CHMP ultimately brought the demise of AMT, which in April passed its assets to its successor company uniQure.

For me, personally, this is very rewarding. AAV1 was the first of the new vectors after the initial failed studies with AAV2. It came out of my lab. And this will be the first approved gene therapy product outside of China. To have contributed by developing the technology that made that possible, that’s rewarding for our group, for all the people who worked on that over the years. We take pride in having contributed to that.

How significantly will this diminish morbidity and mortality of the disease? Pancreatitis can be lethal and any intervention that decreases its incidence is very important. Another important aspect of this milestone is that it sets the precedent for regulatory approval for a gene therapy product in the West. The precedent of an approved AAV product is going to help enormously in the further business development and commercialization of gene therapy.

Why is Glybera the first gene therapy ever approved in the Western world? I think because AMT was the strongest of the second-generation companies, it was well capitalized, and it picked a disease that theoretically one could demonstrate efficacy with as few as 20 to 25 subjects. They had the right technology and the right disease with enough money to carry them to the goal line.

Looking ahead, is the next step approval by FDA? And will they approve it? I don’t really know. I would guess uniQure is trying to partner with someone in the U.S. who may be better positioned to take this forward to FDA. It’s unclear when, or if, we’ll see an approval for Glybera in the U.S.

An operator installs a chromatography column containing an AAV-specific affinity matrix in uniQure’s GMP facility. This affinity matrix has a high capacity to capture AAV vectors derived from filtered cell culture campaigns, and remove undesirable cellular and growth media components. This technology has been developed by uniQure to purify AAV products such as Glybera in a very efficient manner.

James M. Wilson, M.D., Ph.D. ([email protected]), is professor of pathology and laboratory medicine at the University of Pennsylvania. He is also editor of Human Gene Therapy, Human Gene Therapy: Methods, and Human Gene Therapy: Clinical Development, all published by Mary Ann Liebert, Inc.

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