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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Pharmacodynamics-based approach for efficacious human dose projection of BMS-986260, a small molecule transforming

Karen E Parrish1, Jesse Swanson1, Lihong Cheng1

  • 1Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA.

Biopharmaceutics & Drug Disposition
|December 23, 2020
PubMed

Insights

BMS-986260, a novel TGF-βR1 inhibitor, showed promising preclinical antitumor activity. However, mechanism-based cardiovascular findings in rats led to its termination, highlighting safety challenges in TGF-β pathway drug development.

Area of Science:

  • Oncology
  • Pharmacology
  • Drug Development

Background:

  • Transforming growth factor beta (TGF-β) is a cytokine implicated in tumor biology due to its immunosuppressive effects.
  • Targeting the TGF-β pathway is a strategy for cancer therapy, leading to the development of various drug modalities.
  • BMS-986260 is a small molecule inhibitor targeting TGF-β receptor 1 (TGF-βR1) kinase.

Purpose of the Study:

  • To characterize the preclinical pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-986260.
  • To project a clinically efficacious dose for BMS-986260 based on preclinical data.
  • To evaluate the antitumor efficacy of BMS-986260 in a preclinical cancer model.

Main Methods:

  • In vivo PK and distribution studies were conducted in mouse, rat, dog, and monkey.
  • Efficacy studies were performed in the MC38 murine colon cancer model.
  • Target engagement was assessed by measuring SMAD2/3 phosphorylation in whole blood.

Main Results:

  • Human PK was predicted from preclinical species, with an estimated human clearance of 4.25 ml/min/kg.
  • BMS-986260 demonstrated durable antitumor responses at tested doses.
  • Projected efficacious doses were 600 mg once daily or 210 mg twice daily with a drug holiday.

Conclusions:

  • BMS-986260 exhibited favorable preclinical PK and demonstrated antitumor efficacy.
  • Species differences in SMAD2/3 phosphorylation were observed, impacting dose projection.
  • Mechanism-based cardiovascular toxicity in rats led to the termination of BMS-986260 development.
Keywords:
PK/PDTGF-βTGF-β receptor inhibitionhuman efficacious dose projectionpreclinical PK

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