Ziftomenib
Menin Inhibitor
Tipifarnib
Farnesyltransferase Inhibitor
Ziftomenib in Patients with Acute Myeloid Leukemia (AML)
Ziftomenib is an oral investigational drug candidate that we are developing for treatment of genetically defined AML patients with high unmet need.
Ziftomenib blocks the interaction of two proteins called menin and KMT2A/MLL that, together, are critically important for survival, growth and proliferation of certain kinds of leukemia cells.
We have generated preclinical data that support the potential anti-tumor activity of ziftomenib in genetically defined subsets of acute leukemia, including those with rearrangements or partial tandem duplications in the KMT2A gene as well as those with oncogenic driver mutations in genes such as NPM1.
Our preclinical data support the hypothesis that ziftomenib targets epigenetic dysregulation and removes a key block to cellular differentiation to drive anti-tumor activity.
We believe ziftomenib has the potential to address approximately 35% of AML, including NPM1-mutant AML and KMT2A-rearranged AML.
We are currently conducting a Phase 1/2 clinical trial, which we call KOMET-001, in patients with relapsed or refractory AML.
View research on ziftomenib (menin inhibitor).
Tipifarnib in Patients with HRAS Mutant Head and Neck Squamous Cell Carcinoma (HNSCC)
Tipifarnib is an oral, investigational drug candidate we are evaluating in patients with certain head and neck cancers that carry HRAS mutations.
HRAS is a proto-oncogene, which is a normal gene that can become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation and HRAS is mutated and/or expressed in certain head and neck squamous cell carcinoma (HNSCC) tumors.
Although HRAS was discovered more than 40 years ago, no specific therapies have been developed that target tumors with the mutated form of the protein. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme for the activity of HRAS.
The relapsed and/or refractory HNSCC patient population has an overall survival of approximately six to eight months and existing therapeutic options, including new therapies such as immune therapy, typically show a response rate in the range of 10-20 percent.
Tipifarnib has been studied in more than 5,000 oncology patients and was observed to have a manageable side effect profile. Clinical and preclinical data suggest that, in certain selected patient populations, tipifarnib has the potential to provide clinical benefit to cancer patients with limited treatment options.
Encouraging clinical activity of tipifarnib has been observed in patients with HRAS mutant HNSCC tumors. We are conducting a registration-directed clinical trial to evaluate the safety and activity of tipifarnib in patients with recurrent or metastatic HRAS mutant HNSCC.
View research on tipifarnib in HRAS mutant squamous head and neck cancer.
Tipifarnib in Combination with Alpelisib in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC)
The phase 1/2 KURRENT proof-of-concept trial is a currently enrolling, biomarker-defined cohort study designed to evaluate the safety, determine the recommended combination dosing and assess early anti-tumor activity of tipifarnib and alpelisib for the treatment of HNSCC patients whose tumors are dependent on HRAS and/or PI3Kα pathways. Novartis’ alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against the PI3Kα isoform.
HRAS and PI3Kα are co-dependent pathways involved in the development and maintenance of HNSCC in certain patient populations. HRAS represents a key node at the center of HNSCC tumor biology, serving as a central resistance mechanism to other therapies, which reinforces the possibility for combination strategies with tipifarnib. Overexpression of mutant or wild-type HRAS is reported to induce resistance to PI3Kα inhibition and furthermore, HRAS is reported to preferentially activate PI3K versus other pathways. Preclinical data is supportive of tipifarnib in combination with a PI3Kα Inhibitor and its potential to provide a clinically meaningful increase in anti-tumor activity, in both HRAS mutant/overexpressed and PIK3CA mutant/amplified populations of HNSCC.
HRAS mutation/over expression and PIK3CA mutations/amplifications account for up to 50% of HNSCC, according to The Cancer Genome Atlas (TCGA). This represents the opportunity to significantly expand the potential patient population.
View research on tipifarnib in combination with a PI3Kα inhibitor.
Next-Generation Farnesyl Transferase Inhibitor in Patients with Solid Tumors
KO-2806 is a development candidate designed to target innovative biology and address large oncology indications of high unmet need through rational combinations. Multiple advanced lead compounds were identified during a discovery-stage program aimed at developing a next-generation farnesyl transferase inhibitor with improved potency, pharmacokinetic and physicochemical properties relative to tipifarnib. KO-2806 was nominated as our lead development candidate and is currently undergoing investigational new drug (IND)-enabling studies.
Tipifarnib, ziftomenib and KO-2806 are investigational drug candidates and have not yet been approved for use by the U.S. Food and Drug Administration (FDA) or other regulatory authorities.