Aptose longs may have been rattled by a recent announcement from BeiGene ($BGNE) of its plans to advance tyrosine kinase inhibitor zanubrutinib in trials for Waldenstrom macroglobulinemia.

Does zanubrutinib pose a threat to Aptose’s CG’806? I spoke with Aptose CEO William Rice this morning regarding this. He said that zanubrutinib has been on Aptose radar for some time. Its mechanism of action is covalent, while that of CG’806 is non-covalent. While you may think of covalent tyrosine kinase inhibition as “stronger,” CG’806 has proven this not to be the case, that even acting non-covalently, it wields formidable suppression at customary doses of a large variety of cancer-relevant tyrosine kinases.

Like ibrutinib and acalabrutinib, zanubrutinib is a covalent inhibitor of Bruton’s tyrosine kinase(BTK). At this point, BeiGene’s main endeavor is probably to differentiate zanubrutinib from those two competing molecules.

Covalent mechanisms of action for tyrosine kinase inhibitors are felt possibly to facilitate or select for resistance. Indeed, all a cell must do in order for a targeted tyrosine kinase to become resistant to a covalent inhibitor is mutate the single amino acid to which the inhibitor is covalently binding. Non-covalent inhibitors are felt to be less likely thus to cultivate resistance. CG’806 is a non-covalent inhibitor of BTK and quite a few other oncogenic and inflammatory tyrosine kinases.

As we’ve stated before, CG’806 is in a totally different category from other covalent-acting inhibitors of BTK, as well as from several other non-covalent BTK inhibitors also being advanced by other companies to clinic and toward marketing. Aptose poster presentations have consistently demonstrated CG’806 to have far broader inhibitory activity, taking down more kinds of tyrosine kinase targets, than competing non-covalent or covalent BTK inhibitors. CG’806 generally accomplishes this inhibition at extraordinarily low drug concentrations, indeed, low concentration efficacy rarely seen in molecular oncology. Although toxicity studies on CG’806 are incomplete and ongoing, early evidence suggests that CG’806 may accomplish its therapeutic effect with few or none of the side effect downsides of other tyrosine kinase inhibitors (side effects ranging from nausea and bone marrow suppression to asthenia, hypertension and EKG changes). For example, roughly 40 percent of patients initiated on ibrutinib discontinue it within 7 months, generally because of toxicity. Ibrutinib is marketed as Imbruvica by $JNJ, and was developed by Pharmacyclics, which was acquired for $21B by $ABBV in January 2016.

According to Rice, Aptose sees zanubrutinib “[not] as a competitor to CG’806, but rather as a potential molecule for combination therapy with CG’806 in the future.”

Disclosures: Of companies mentioned above, I have a long position in $APTO. I will not trade in $APTO shares for 7 days, reckoned in business days, after this column appears. This column is not a recommendation or solicitation for any reader to buy shares in $APTO, and diligence is due before trading in biotechnology equities. BioPub has no pecuniary relationship with Aptose.