Key Advantages of Covalent Drugs

Since the discovery of aspirin in 1899, covalent drugs have been known to offer a number of potential safety, tolerability and efficacy advantages over conventional non-covalent drugs through multiple mechanisms, including:

  • High selectivity: Covalent drugs have the potential to confer high selectivity to a target by interacting with the unique surrounding structural elements of the protein and establishing a covalent bond to a key residue in the binding site. Leveraging non-covalent and covalent interactions can lead to greater selectivity versus non-covalent compounds, which rely solely on non-covalent binding. This has the potential to reduce the likelihood of non-specific, off-target interactions that often lead to safety and tolerability concerns. 
  • Deep inactivation of target: Upon binding, a covalent inhibitor not only causes inactivation of the target, but may also result in the elimination of the target through normal cellular degradation processes. The diseased cell then either undergoes rapid apoptosis or differentiation into a normal, mature cell. Such transformation has the potential to provide the patient with a durable, lasting benefit.
  • Greater therapeutic window: Covalent inhibitors are designed to create a permanent bond with high affinity and long residence time. Unlike conventional non-covalent drugs, which typically need to be present to provide benefit, covalent drugs have the potential to maintain their effect in the absence of sustained drug exposure. The permanent inhibition of target function upon covalent binding essentially uncouples PD (drug effects) from PK (drug exposure), as target inhibition persists after the drug has been cleared from the system. This property of covalent drugs can potentially lead to lower drug doses and less frequent dosing regimens versus non-covalent approaches.  Figure 1 below highlights the potential PD and PK benefits of an FDA approved covalent BTK inhibitor (ibrutinib). In particular, the model shows the ability of a covalent inhibitor to quickly achieve maximum target engagement and sustain inhibition while the drug is rapidly cleared from the body, which further reduces the potential for off-target interactions and non-mechanism-based toxicities. These features have enabled ibrutinib to achieve sustained efficacy with lower exposure and a favorable safety profile.

Our Mission

Our mission is to revolutionize medicine by creating therapies that cure patients of their disease.

We leverage our drug design and operational expertise to create novel covalent small molecules to treat serious and life-threatening diseases. All of our molecules are invented and created in-house. They are highly selective, targeted medicines, that address key mechanisms of our patient’s disease progression. We have built an R&D engine that has so far produced three novel, covalent inhibitor programs that are currently in preclinical and clinical development. Our team is engaged in all phases of drug discovery and development, including target selection, small molecule design, and preclinical and clinical studies to develop our innovative medicines.
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