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Deciphera Pharmaceuticals, a clinical-stage biotechnology company focused on
developing advanced kinase inhibitor treatments targeting the tumor cell and
the tumor microenvironment, today announced that preclinical data on the
company's growing pipeline of next generation kinase inhibitors were presented
at the American Association for Cancer Research (AACR) Annual Meeting 2015.
The presentations include data on Deciphera's most advanced proprietary drug
candidates including altiratinib, a potent and balanced inhibitor of
MET/TRK/TIE2 and VEGFR2 kinases and rebastinib, a TIE2 inhibitor, and on the
Company's work with Eli Lilly and Company on pan-RAF inhibitors.
"We are excited to share the results from these studies of our novel kinase
inhibitor drug candidates with the oncology community at AACR. These data
demonstrate the unique attributes offered by our advanced small molecule
kinase inhibitor therapeutics to block key cancer signaling mechanisms,
preventing the ability of tumor cells to thrive and spread," said Michael D.
Taylor, Ph.D., Deciphera's President and Chief Executive Officer.
In a poster presentation entitled "Altiratinib is a potent inhibitor of TRK
kinases and is efficacious in TRK-fusion driven cancer models," Deciphera
researchers in collaboration with the Memorial Sloan Kettering Cancer Center
demonstrated that altiratinib potently inhibited TPM3-TRKA and ETV6-TRKC
fusion protein activation and cell proliferation in tumor cell lines. TRK
kinases are implicated in a variety of cancers in which TRK gene fusions have
been shown to drive tumor growth. Combined with its inhibition of key tumor
microenvironment targets including MET, TIE2, and VEGFR2 kinases, altiratinib
provides the potential to durably treat cancers in patients harboring these
TRK fusions. Altiratinib is currently in a Phase 1 clinical trial in patients
with solid tumors.
* In the KM-12 colorectal xenograft model, altiratinib dosed at 15 mg/kg
altiratinib inhibited TPM3/TRKA fusion protein phosphorylation by >95% for
more than 12 hours, and in a multi-day efficacy study led to significant
tumor growth suppression. Similarly, in a ETV6/TRKC fusion protein
xenograft study, altiratinib daily administration led to significant tumor
regression.
In a poster presentation entitled, "Rebastinib potently inhibits function of
perivascular TIE2 expressing macrophages in vitro and in vivo," Deciphera
researchers in collaboration with the Albert Einstein College of Medicine
reported that rebastinib, a selective TIE2 kinase inhibitor with picomolar
potency, completely blocked TIE-2 expressing macrophage (TEM)-induced tumor
cell invasion. TEMs are a population of highly protumoral macrophages that
facilitate tumor growth, angiogenesis, invasion, and immunosuppression.
Rebastinib has completed a first-in-human study and will enter a Phase 1b
study in the second half of 2015.
* When evaluated in vivo in a mouse breast cancer model, rebastinib dosed at
10 mg/kg orally twice weekly was sufficient to impair tumoral TEMs,
resulting in significant reduction in tumor vascular permeability and
ablation of tumor cell invasion as quantified by circulating tumor cells.
In a poster presentation entitled, "Mouse PDX trial suggests combination
efficacy of Raf and EGFR inhibition for colorectal cancer with BRaf or KRas
mutation," preclinical results were presented on LSN3074753, a pan-RAF
inhibitor developed by Deciphera in collaboration with Lilly. This program is
currently in Phase 1 clinical development. Synergy was found in a subset of
colorectal cancers by combining the pan-RAF inhibitor, which has been shown to
inhibit mutant KRAS and BRAF tumor cell drivers that occur in approximately
70% of colorectal cancer patients, with the anti-EGFR antibody cetuximab.
* When evaluated in a collection of 78 patient-derived xenograft models of
colorectal tumors, the overall disease control rate (DCR) in the
combination arm was 50% (39/78), while cetuximab or LSN3074753 alone had
an overall DCR of 24 or 18%, respectively. Further statistical analyses
revealed that BRaf mutations are the best predictor of combination
synergy. BRaf or KRas mutations were also significantly associated with
combination synergy.
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