According to a paper published by Protalix scientists in 2007, glycosylation of their protein is markedly different than glycosylation of Cerezyme. This sounds potentially very problematic, as glycosylation affects interaction with tissues and cells and also can be responsible for immugenicity. Has anyone taken a close look at this?
In today's BioWorld Today (9/21/10), there is an article talking about FDA set to hold a meeting on biosimilars probably in November. Deutsche Banks analyst is quoted:
"Many complex biologics have sugar chains that impact their efficacy and safety, and she noted that the FDA has made several statements over the years suggesting a primary concern that biosimilars have the same sugar structure for interchangeability..."
It is quite clear that Uplyso does not have same sugar structure as Cerezyme.
Additionally, the paper reports differences in the enzyme active site based on crystallography studies. Agree with previous that immunogenicity issues have not been addressed. Company hasn't done clinical trials of sufficient size to look into this.
Great find. Took a look at this paper. Its clear there are major differences between glycosylation patterns of their product vs. competitors. Figure 3 in particular is revealing, showing the various major glycan structures produced by carrot cells that are quite different than the glycan structure on the approved drug. While yes it can bind to the targeted macrophage, the problem is going to be immunogenicity and binding to undesired cell populations. This product will have novel plant carbohydrate epitopes exposed on it. This is a real problem. The company has not done clinical trials of sufficient size to assess these kinds of potential immunogenicity problems, so you have to wonder when the company will have sufficient data to address this. Furthermore, the paper reports differences in the enzyme active site based on crystallography. In short, these are 2 different molecules that represent two distinct variations of the GCD enzyme. Don't know of FDA precedents where this didn't matter, but if others do please share that info.
The glycosylation of the PLX enzyme is different.
From what I remember, the carrot cell naturally produces an enzyme with terminal mannose residues. Cerezyme has a different glycosylation pattern because it is produced in a mammalian (hamster) cell. However, as part of the purification process, Genzyme clips several sugars off of the enzyme so that mannose is the terminal sugar residue (I believe they use neuraminidase and hexoseaminidase). The point is to terminate the glycosylation with mannose so it will bind to the mannose receptor on macrophages.