Genzyme's Myozyme knocked back after scale-up

The US Food and Drug Administration has rejected an application from biotechnology firm Genzyme to make its already-approved, protein-based drug Myozyme in larger batches. The regulator cited small structural differences in the biologic drug produced by the scaled-up process. 

The decision has sparked debate on the FDA’s criteria for approving biologic drugs, and its position on approving generic copies of off-patent biologics. 

Myozyme is an enzyme-replacement therapy, the first drug developed to treat Pompe disease, a rare genetic disorder that causes muscle degeneration, ultimately leading to death. US-based Genzyme received FDA approval for Myozyme in April 2006. However, the material approved by the FDA was made in 160 litre batches. The company says it is now unable to satisfy demand for the drug by making it at this scale, so has requested FDA approval for the same drug made on a 2000 litre scale. 

But the data Genzyme provided to the FDA for approval showed differences in the carbohydrate component of the drug, which is involved in uptake of the enzyme into muscle tissue. The FDA considered these differences significant enough to consider the 2000-litre-batch material a new drug, requiring its own clinical trial data. 

However, the data on the larger-scale version of Myozyme has already been seen by the European Medicines Agency (EMEA), who approved that drug for use in Europe in March 2006. 

Conservative decision

’We’re disappointed by the FDA’s decision,’ says Henri Termeer, Genzyme’s chief executive officer. The decision ’does indicate a clear difference to how the EMEA, and the Japanese authorities, look at these matters of similarity. The FDA is clearly more conservative in this regard.’ 

Genzyme has already completed a clinical trial using the larger batch material, so anticipates receiving approval by the end of 2008, following a priority review by the FDA. However, the decision has sparked speculation about the regulator’s likely stand on generic copies of biologic drugs. Unlike in Europe, the US is yet to establish a framework by which generic drug makers can seek approval to sell copies of off-patent biologic drugs, or ’biosimilars’. Unlike traditional, small molecule-based drugs, it is often difficult to prove that a biologic generic has an identical make-up to the original drug. 

’Clearly the FDA is setting a bar here,’ said Alison Lawton, head of regulatory affairs at Genzyme, when asked what the regulator’s decision meant for it’s likely stance on biosimilars. ’We have considerable clinical experience, with hundreds of patients already on 2000 litre material around the world. Yet, because of carbohydrate differences, the FDA has decided that these are two separate products. I think it sends a very loud message and sets a very high bar, as far as biosimilar products.’ 

’This decision gives an idea of the amount of work companies will have to do to simply move their own product from one site to another - so its going to be at least as difficult for new companies to make a biosimilar,’ UK-based biopharmaceuticals consultant Malcolm Rhodes told Chemistry World. 

No precedent

However, Lincoln Tsang, who chairs the UK BioIndustry Association’s regulatory advisory committee, thinks that the FDA’s handling of new versions of biologics produced by different processes will not necessarily inform its stance on biosimilar generics. And he adds that US, European and Japanese regulators have a shared set of technical guidelines on how to assess product comparability as a result of process change. ’The technical guidelines have been put in place quite recently [2005],’ he says, ’and before that regulators applied their own guidelines. I would have thought their approaches will now essentially converge.’ 

’However, you do see different outcomes even within agencies, because assessment is individual, and is based on judgement of the data. We simply do not know if one regulator is stricter than the others,’ adds Tsang.   

The EMEA told Chemistry World that it is not in a position to make comments on the approaches taken by other regulatory authorities - and that its own decisions on evaluating similar biological medicines are made in a case-by-case approach. The FDA was unable to comment. 

James Mitchell Crow