RXC005 (Jaypirca^TM (pirtobrutinib)) Reversible BTK inhibitor

The Bruton’s tyrosine kinase (BTK) inhibitor programme was sold to Loxo Oncology (now part of Eli Lilly) in July 2017 for $40 million, and pirtobrutinib (originally RXC005, then LOXO-305, now Jaypirca^TM) has been approved under the FDA’s Accelerated Approval pathway for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase (BTK) inhibitor. Whilst Redx is not due to receive any future payments in relation to RXC005, the scientific story underlines our track record for discovery and delivery of valuable molecules that can succeed in the clinic, resulting from our rigorous target selection and world class scientific delivery.

The discovery of RXC005: targeting a BTK inhibitor resistance mutation

The impressive clinical efficacy observed with first generation BTK inhibitor ibrutinib (Imbruvica®) highlighted the importance of BTK as a clinically validated drug target across a range of haematological malignancies. The potency and potential of approved first-generation BTK inhibitor ibrutinib and second-generation inhibitors, acalabrutinib (Calquence®), zanubrutinib (Brukinsa®), 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 are associated with rapid progression and poor outcomes.

Our scientists, using their expertise on irreversible BTK inhibitors, initiated a reversible BTK inhibitor programme, following the identification of the C481S mutation. 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. More information can be found here.

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).

Jaypirca^TM is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.