Oncology Pipeline

Loxo@Lilly aims to create medicines that make life better for all those affected by cancer around the world. Bringing together the focus and spirit of a biotech with the scale, resources, and heritage of Lilly, our team is focused on rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating oncology medicines that unequivocally show early signs of clinical activity and will matter to patients.

BTK Inhibitor

Pirtobrutinib

Estupiñán HY, et al¹; Mato AR, et al²; Brandhuber B, et al³; Alsadhan A, et al⁴; Gomez EB, et al⁵; Gomez EB, et al⁶

Target

Bruton's tyrosine kinase (BTK) inhibitors represent a major therapeutic advance in the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and B-cell malignancies by inducing responses.^7-12 BTK is critical for the propagation of B-cell receptor signaling and is upregulated in many B-cell malignancies as compared with normal B-cells. BTK inhibition, both in vitro and in vivo, decreases proliferation and survival signals.⁷

Molecule

Pirtobrutinib is an investigational, oral, highly selective (over 300-fold more selective for BTK vs 98% of 370 non-BTK-kinases), non-covalent (reversible) BTK inhibitor.^2,3 It possesses nanomolar potency independent of BTK C481 status in enzyme and cell-based assays.^2,3,6 Pirtobrutinib has been shown in preclinical studies to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases.²

Clinical Development

Pirtobrutinib is being investigated in clinical trials in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, and non-Hodgkin’s lymphoma.

References

Estupiñán HY, et al. Front Cell Dev Biol. 2021;9:630942.
Mato AR, et al. Lancet. 2021;397(10277):892-901.
Brandhuber B, et al. Clin Lymphoma Myeloma Leuk. 2018;18:S216.
Alsadhan A, et al. Clin Cancer Res. 2020;26(12):2800-2809.
Gomez EB, et al. Blood. 2023;142(1):62-72.
Gomez EB, et al. Blood. 2019;134(suppl 1):4644.
Woyach JA, et al. J Clin Oncol. 2017;35(13):1437-1443.
Byrd JC, et al. N Engl J Med. 2016;374(4):323-332.
Mato AR, et al. Blood. 2016;128(18):2199-2205.
Rule S, et al. Haematologica. 2019;104(5):e211-e214.
Wang M, et al. Leukemia. 2019;33(11):2762-2766.
Noy A, et al. Blood. 2017;129(16):2224-2232.

Pirtobrutinib Mechanism of Action

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The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

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