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Portfolio / Product pipeline

Crenolanib (CP-868-596)

Next Generation Inhibitor of Receptor Tyrosine Kinases

  • Unique chemo-type with benzimidazole backbone
  • Preferentially inhibits phosphorylated receptors
  • Activity against wild type & mutant receptors
  • Specificity for PDGFRα, PDGFRβ and FLT3
  • No activity against VEGFR or FGFR

The chemical name of crenolanib besylate is 4-piperidinamine, 1-[2-[5-[(3-Methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-, monobenzenesulfonate.

Preclinical

Crenolanib besylate is an orally bioavailable, selective small molecule inhibitor of type III tyrosine kinases, with nanomolar potencies against Platelet-derived growth factor receptors (PDGFR), isoforms PDGFRα and PDGFRβ, and the FMS-related tyrosine kinase 3 (FLT3). Besides PDGFR and Flt3, crenolanib does not inhibit any other know RTK (VEGFR, FGFR) or any other serine/threonine kinase (abl, raf) at clinically achievable concentrations

The important aspect about the constitutively active point mutations of FLT3 (D835V/Y) and its analogous mutation in PDGFRA (D842V) and c-KIT (D816V) are that they are resistant to both FDA approved and clinical developmental stage TKIs. The acquisition of these point mutations in the FLT3 (ITD and TKD), PDGFRA, and c-Kit gene was shown to induce constitutive activation of the receptor- and ligand-independent cell growth in different cell lines. These mutations are hyper-sensitive to crenolanib. Table below provides a summary of the potency of crenolanib for inhibiting these constitutively activating mutations of Type III receptor kinases PDGFRA and FLT3.

Crenolanib

crenolanib2

Clinical

Crenolanib has been clinically evaluated in the Phase I setting as a single agent and in the Phase Ib setting in combination with docetaxel and axitinib.

Phase I trial (single agent), Lewis N, et al. 2009

  • Dose range: 100mg QD to 340mg QD
  • Most AEs were grade 1 or 2
  • Only grade 3 or 4 AEs were
    • Nausea/vomiting
    • Reversible liver enzyme elevations

Phase Ib trial (combination), Michael M, et al. 2010

  • Combination with full doses of docetaxel axitinib
  • Safely combined with non-overlapping PK profile

There are three ongoing clinical trials of crenolanib in the US:

  1. A Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas (NCT01229644)
  2. A Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of GIST (NCT01243346)
  3. Phase I Study of Platelet Derived Growth Factor Receptor (PDGFR) Inhibitor, Crenolanib in Newly Diagnosed and Recurrent High-grade Pediatric Glioma Including Diffuse Intrinsic Pontine Glioma (NCT01393912)

The anticipated trials of crenolanib include Phase II trials in:

  • Acute Myeloid Leukemia
  • Ovarian Cancer