Small Molecule PEGylation: An Idea Ready For Prime Time 
Posted by Carlos on Sep 17, 2014

At Lacerta Bio, we’re big believers in the therapeutic benefits of drug delivery in its many forms.

Today, another drug delivery effort earned an FDA approval. In this case, it’s naloxegol from Nektar (and its partner, AstraZeneca). Naloxegol was approved for the treatment of opioid-induced constipation.

Naloxegol is a highly interesting molecule because it consists of a molecule of naloxol to which a 7-mer liner PEG is attached.

Now the PEGylation of peptides and proteins is a well-established method for conferring extended half-lives and preferential uptake properties to these molecules.

So why PEGylate small molecules?

There are a few reasons:

Increase aqueous solubility – Short Strands of PEG are highly water-soluble, and they can “pull” less soluble drugs into solution, thereby enhancing oral bioavailability.

Decreased toxicity – PEGylated small molecules are generally cleared hepatically. So reducing renal clearance (and hence renal toxicity) can be addressed via PEGylation. Add enough PEG, and oral absorption could be dramatically reduced, if that is what is desired.

Interestingly, the PEGylation of small molecules is not restricted to parenteral drugs. Oral drugs, such as acyclovir, may provide incremental clinical and safety benefits through PEGylation.

A terrific review article from 2013 (large PDF file) discusses the 20-25 PEGylated small molecules which are in various stages of development (of which four were in the clinic at the time of publication).

A few of them stand out as interesting in our mind:

PEG-ironotecan (NKTR-102) – Nektar has developed a PEGylated version of the cancer drug ironotecan. It is currently in a variety of clinical studies for metastatic breast and other cancer indications. The increase in molecular weight due to PEGylation results in a 300-fold increase in preclinical efficacy compared with native drug. Clinically, drug half life is extended to the point where dosing can be performed on a weekly schedule, and with a much higher maximum tolerated dose.

PEG-SN38 (EZN-2208) –  SN38 is a camptothecin with poor water solubility. In fact, it is so poor that intravenous administration is not feasible. Enzon developed a PEGylated version, and reported promising Phase II results in metastatic breast cancer.

PEG-docetaxel (NKTR-105) – Docetaxel is a highly effective antineoplastic agent. However, clinical use is limited due to side effects. A PEGylated version similar to PEG-ironotecan was prepared, and demonstrated superior Preclinical performance compared to native drug. It appears that Nektar has since dropped this program.

The notion of solving PK or other problems with PEGylation has been extended beyond the cancer drugs. Antivirals (such as PEG-acyclovir), antifungals (PEG-amphotericin B), and immunosuppressants (PEG-tacrolimus) are all small molecules which may benefit from PEGylation.


An interesting idea is to use PEGylation to reduce CNS exposure to drugs such as opioids and anti-histamines. Thus, a PEGylated form of diphenhydramine could be a highly effective anti-histamine without the sedation associated with the native drug.

What is really exciting about this approach is that the PEGylation chemistries have become far more sophisticated. As a result, very precise chemistries can be used to generate PEGylated small molecules that are much easier to synthesis and purify.

Currently, Nektar is at the forefront of this approach. But it is likely that several academic researchers and companies (such as BiogenIdec) will continue to explore this approach to solving problems associated with established small molecules.

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