The discovery of RXC005: Picking the right drug target and delivering world-class medicinal chemistry

The impressive clinical efficacy observed with first generation Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica®) highlighted the importance of BTK as a clinically-validated drug target across a range of haematological malignancies. The potency of first-generation BTK inhibitor ibrutinib, and second-generation inhibitors, acalabrutinib (Calquence®), zanubrutinib (BGB-3111), tirabrutinib (GS-4059), rely on the formation of a covalent bond with a cysteine residue (C481) of BTK active site, which leads to an irreversible inhibition of the kinase activity. As such, any mutation of this amino acid (C481) will interfere with the drug binding mode, and thus reduce the effectiveness of irreversible BTK inhibitors.

C481 mutations in BTK have been reported in chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL) patients. The Ohio State University (OSU) has demonstrated that 80% of patients relapsing CLL will have the C481S mutation following treatment with Ibrutinib. For both CLL and MCL, patients developing resistance to ibrutinib is associated with rapid progression and poor outcome.

Redx scientists, using their expertise on irreversible BTK inhibitors, initiated a reversible BTK inhibitor programme, following the identification of the C481S mutation by Woyach’s group., This programme delivered RXC005 (REDX08608), a novel, potent and highly selective, reversible inhibitor of BTK, which was equally as effective at inhibiting non-mutated BTK (wild-type BTK) and C481S-mutated BTK. As such, RXC005 aimed to overcome such resistance mechanisms to first and second-generation inhibitors, whilst retaining activity where irreversible inhibitors such as ibrutinib are inefficient.

RXC005 was successfully nominated as a drug candidate in October 2016 and the preclinical data supporting this decision were presented at the 58th American Society of Hematology (ASH) in December 2016 (Guisot et al., 2016) and the XVII International Workshop on Chronic Lymphocytic Leukemia (iwCLL) in May 2017 (Guisot et al., 2017). RXC005 was sold to Loxo Oncology in July 2017 for $40 million, RXC005 is now Loxo-305.

Although we are no longer due to receive any future payments in relation to RXC005, the scientific story of this programme highlights our track record for delivery of great science underpinned by rigorous target selection and world class scientific delivery, which we continue to build upon as we drive forward our new Redx programmes.