Bioavailability Challenges Persist
The industry is always looking for new technologies to make synthesis and manufacture more economical, said Dr. Lax of The PolyPeptide Group, “but I think there is some reluctance to move away from current technologies. Fmoc chemistry in general works really well. I think most changes in the near future are going to be made through optimizing the chemistry we have.”
Improving delivery and bioavailability remain pressing needs and areas of active investigation. “Everybody is trying to find peptides that are more potent so the dose is lower, or they are trying to extend the biological half-life—mainly by developing long-acting release methods or conjugating peptides to nonpeptidic moieties that give them more extended biological activity,” according to Dr. Lax.
The obvious one is PEGgylation. This technology has been employed with proteins for a very long time. Dr. Lax notes the first PEGylated peptide (peginesatide from Affymax) was approved this year. “I am sure there will be others,” he said.
However, there are issues with PEGylation. One is the accumulation of PEGs in tissues after chronic administration because it is not easily removed from the body. “We’ll see a move to discover alternative large conjugates that are more amenable to biological degradation,” said Dr. Lax.
Detection of impurities is another challenge. “The peptides we’re making typically have a molecular weight in the range of 2,000–4,000 Daltons and PEGs are typically 20–40K Da. Once you attach a peptide to the PEG, any impurities already in the peptide or generated during the conjugation are masked by the broad PEG peak and cannot be detected analytically by HPLC methods.”
Until recently, said Dr. Lax, the approach to manufacturing PEGylated peptides was to prepare the peptide as purely as possible, demonstrate the high purity analytically, and then PEGylate it. “The logic being that the peptide was pure before I attached the PEG and therefore it must be pure after I attached it. I think the regulatory authorities no longer totally buy into that.”
There is currently no “really good technology for detaching the PEG” and Dr. Lax said he believes we may in the future see PEGs that are reversibly attachable to the peptides or that can be detached using some chemical or enzymatic technology. This would allow us to recover the peptide in order to determine its impurity profile.