PTMs and Biosimilars
PTMs, particularly glycosylation, will play a critical role in how biosimilars (also at times called follow-on biologics and generic biotherapeutics) are eventually approved.
The Food and Drug Act, under which small molecule drugs are approved, does not apply to biologicals. Neither does the Hatch-Waxman act of 1984, which created the generic drug industry (although earlier generic bio-drugs like insulin and human growth hormone were grandfathered under the drug law).
Since the idea of biosimilars arose more than a decade ago, the major stakeholders —with the exception of potential developers of generic biotherapeutics—have done their best to cloud the scientific issues surrounding these products. Since innovator companies are not obliged to share information with potential competitors, the latter are left to their own devices in designing processes that will faithfully recreate blockbuster biotherapeutics. But as everyone knows, in biotech the product is the process, and nowhere is this more evident than in PTMs.
Genzyme’s recent experience illustrates how seriously the FDA takes the issue of glycosylation and bioequivalence. Earlier this year, Genzyme was informed by the agency that the company’s Myozyme® enzyme replacement therapy for Pompe disease produced at 2,000 L scale was not equivalent to the drug manufactured in 160 L bioreactors. FDA asked for a separate Biologics License Application for the larger-scale product even though it is already approved in 40 countries, and had been shown to be “clinically effective and safe” in a 900 patient clinical study.
FDA based its decision on differences in glycosylation between products produced at the two scales. It is noteworthy that in public statements comparing products manufactured at the two scales, Genzyme merely said they were both safe and effective, avoiding any implication that the two were equivalent or bioequivalent, a term that bristles U.S. regulators. An FDA committee recommended in October 2008 that Myozyme 2000 be granted accelerated approval.
Katheryn Symank, an analyst with Frost and Sullivan, says that the Myozyme experience illustrates how far FDA will go to drive home the point that PTMs matter.
“FDA is still trying to invent an approval pathway for these drugs. Even the name they currently use, biosimilars, suggests inherent differences.” Symank is hopeful that the incoming administration, which promises national science initiatives, will help get the ball rolling with biosimilar approvals.
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.”