Evolution of Biosimilars
Glycosylation is a “huge scientific issue” in the evolution of biosimilars, says Bob Roth, M.D. Ph.D., medical director at the Weinberg Group, an international scientific and regulatory consulting firm. “It’s virtually impossible to make a protein with the same glycosylation patterns in two different processes. Even cell culture conditions can change glycosylation patterns.”
FDA is undoubtedly conscious here of other instances where seemingly trivial differences in PTMs cause serious side effects. One striking example is pure red cell aplasia, a rare, serious immune reaction to erythropoietin believed to arise from reactions to “unfriendly” glycosylation and/or sialylation patterns.
Harry M. Meade, Ph.D., svp for R&D at GTC Biotherapeutics, agrees that PTMs are at the heart of the biosimilars issue. GTC pioneered the production of therapeutic proteins in the milk of transgenic animals. “The PTMs in goat milk are, of course, mammalian, basically of the same structure as that found on human proteins, which puts them way ahead of plant sugars.”
As proof, he posits that there have never been adverse immune responses to recombinant proteins from milk (although issues have arisen with contaminating native animal proteins). Despite the fact that “goat milk proteins are just as human-like as those produced from CHO cells,” transgenics has yet to deliver on its promise, mostly due to regulators’ lack of familiarity with the technique and safety concerns.
Most experts agree that the impact of process on PTMs, and the potential of modifications to affect efficacy and safety, demands precisely the level of scrutiny that biosimilars are experiencing today from U.S. regulators. There are simply too many unknowns to act otherwise.
Dr. Roth feels that diligent oversight will eventually lead to a regulatory pathway for biosimilars that considers products on a case-by-case basis. “It will certainly not be the same as for generic drugs,” he says. Demonstrating what the differences are, quantifying them, and correlating them to clinical (safety or efficacy) outcomes will help the approval process.
“Developers will need to show which PTM differences are trivial before arguing which clinical development steps can safely be skipped.” It is almost certain, moreover, that any shortcuts will need to be justified empirically, in animal models and human subjects. “Presumably, for certain products, some early human testing might be avoided, and perhaps some of the late-stage testing as well, but nobody will be able to predict because nobody knows for sure.”