PKC (IDE196)


Our most advanced pipeline program is IDE196, a potent and selective small molecule inhibitor of PKC, a protein kinase that functions downstream of the GTPases GNAQ and GNA11. We hold an exclusive, worldwide license to IDE196 from Novartis, which is conducting a Phase 1 clinical trial in metastatic uveal melanoma, a cancer of the eye with a high frequency of GNAQ or GNA11 gene mutations. We plan to initiate our own Phase 1/2 basket trial to evaluate IDE196 in patients with metastatic solid tumors harboring GNAQ or GNA11 mutations, including metastatic uveal melanoma, and potentially other mutations and gene fusions that activate the PKC signaling pathway.

GNAQ / GNA11 Alterations in Solid Tumors

PKC belongs to a family of closely related protein kinases that are involved in various aspects of signal transduction, such as transmitting extracellular growth factor or cytokine signals to other protein kinases involved in cellular proliferation or transcription regulation. PKC is important for signal transduction and survival of cells with constitutively active mutations in GNAQ or GNA11. Inactivation of PKC by specific inhibitors or reduction in protein expression using RNA all highlight the essential role of PKC in cells with GNAQ or GNA11 mutations.

Activating mutations in GNAQ or GNA11 are found in approximately 90% of uveal melanoma patients, resulting in a dependency on PKC activity which we believe may sensitize these tumors to the effects of IDE196. Uveal melanoma is a cancer of the eye and the most common primary intraocular malignancy in adults, with an annual incidence of approximately 3,500 in the United States. Treatment of the primary lesion involves radiation therapy, laser therapy and/or removal of the affected eye, and is effective in preventing local recurrence in over 80% of cases. However, approximately 50% of uveal melanoma patients treated in this manner will eventually develop metastatic disease, most commonly in the liver.

Patients with metastatic uveal melanoma have a very poor prognosis, and there are no FDA approved therapies for this disease. Metastases are most frequently localized to the liver where curative surgical approaches are rare, and chemotherapy or immunotherapy has limited efficacy. Without treatment, median overall survival of patients with metastatic uveal melanoma is approximately ten months. A meta-analysis of 29 Phase 2 clinical trials of various therapies in metastatic uveal melanoma from 1988 to 2015 demonstrated no improvement in clinical response, with a medium progression free survival of 3.29 months, median overall survival of 10.2 months, and a 1-year overall survival rate of only 43%. The poor prognosis associated with metastatic disease and the lack of effective therapies highlight the need for novel therapeutic approaches that specifically target metastatic uveal melanoma.

Mutations in GNAQ or GNA11 Activate the PKC Signaling Pathway
GNAQ and GNA11 Mutations

Source: TCGA Data in cBioportal

PKC Gene Fusions

Source: TCGA Data in cBioportal

In addition to uveal melanoma, mutations in GNAQ or GNA11 have also been observed at lower frequencies across other solid tumors. PKC gene fusions, where a portion of an unrelated gene fuses to the kinase domain of PKC as a result of a chromosomal translocation, have also been identified from sequence analyses of tumors. These fusions may result in the overexpression and constitutive activation of the PKC kinase. Preclinical validation of the functional relevance of GNAQ or GNA11 mutations in solid tumors, and of PKC fusions in solid tumors is ongoing.

Additionally, a recent study has implicated PKC as a resistance mechanism acting downstream of EGFR tyrosine kinase inhibitors (TKIs). This suggests a potential opportunity for IDE196 in combination with an EGFR inhibitor in NSCLC patients having tumors resistant to an EGFR inhibitor, where that resistance is mediated by PKC. Preclinical validation of this opportunity is ongoing.

Summary of Preclinical and Clinical Data

IDE196 is a potent and selective small molecule inhibitor of PKC. Preclinical data illustrates that IDE196 is potent against both classical isoforms and novel delta, epsilon, eta and theta isoforms of the PKC kinase family with good selectively relative to other kinases.

IDE196 demonstrated early clinical activity and tolerability in an ongoing Phase 1 clinical study being conducted by Novartis in patients with metastatic uveal melanoma (MUM). This clinical trial is entitled “A Phase I, multi-center, open-label, study of LXS196, an oral protein kinase C inhibitor, in patients with metastatic uveal melanoma” ( Identifier: NCT02601378).

IDEAYA will continue clinical development of IDE196. In addition to MUM, IDEAYA will also explore a tumor agnostic basket study of solid tumors with mutations of GNAQ and GNA11. Both GNAQ and GNA11 mutations are listed in multiple diagnostic panels, including the FoundationOne CDx™ NGS panel, FoundationOne™Liquid Biopsy Panel, and the Guardant360® Liquid Biopsy panel.

IDEAYA is also evaluating the potential use of IDE196 to target various PKC fusion isoforms.