Voruciclib

The CDK family of proteins are important cell cycle regulators responsible for the control of cell proliferation, differentiation, apoptosis, and DNA repair. CDK9, one of several members of the CDK family of proteins, functions as a gene transcription controller and is also involved in regulating protein degradation. Specifically, CDK9 is a promising target to treat a range of cancers because of its role in controlling two other proteins often dysregulated in cancerous cells:

• CDK9 is a transcriptional regulator of the myeloid leukemia cell differentiation protein ("MCL1"), a member of the family of anti-apoptotic proteins which, when elevated, may prevent the cell from undergoing cell death. Inhibition of CDK9 blocks the production of MCL1, which is an established resistance mechanism to the B-cell lymphoma ("BCL2") inhibitor venetoclax (marketed as Venclexta®).
• CDK9 is a transcriptional regulator of the MYC proto-oncogene protein ("MYC") which regulates cell proliferation and growth. Upregulation of MYC is implicated in many human cancers and is frequently associated with poor prognosis and unfavorable patient survival. CDK9, in addition to being a transcription factor for MYC, also decreases phosphorylation of MYC protein that is implicated in stabilizing MYC in KRAS mutant cancers. Targeting MYC directly has historically been difficult, but CDK9 is a promising approach to target this oncogene.

Our development program for voruciclib is exploring applications that leverage the role of CDK9 in controlling two proteins often dysregulated in cancerous cells: MCL1 and MYC.

Voruciclib: Inhibition of MCL1

In pre-clinical studies voruciclib shows dose-dependent suppression of MCL1; in December 2017 a study of voruciclib published in the journal Nature Scientific Reports reported that the combination of voruciclib plus the BCL-2 inhibitor venetoclax was capable of inhibiting two master regulators of cell survival, MCL-1 and BCL-2, and achieved synergistic antitumor effect in an aggressive subset of DLBCL pre-clinical models. Additional preclinical studies demonstrate that the inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the BCL-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia. (Sig Transduct Target Ther 5, 17 (2020). https://doi.org/10.1038/s41392-020-0112-3.

The research suggests voruciclib’s potential as an attractive therapeutic target for treating cancers in combination with venetoclax or other BCL-2 inhibitors, to address potential resistance associated with MCL1, and is supportive of our ongoing clinical program evaluating voruciclib. Currently, we are evaluating patients with hematological malignancies in a Phase 1 clinical trial. The trial started with the evaluation of dose and schedule of voruciclib as a monotherapy in patients with relapsed and refractory B-cell malignancies and AML after failure of prior standard therapies to determine the safety, preliminary efficacy and maximum tolerated dose. The trial is now evaluating the dose and schedule of voruciclib in combination with venetoclax, a BCL2 inhibitor, to assess synergies and the opportunity for combination treatments, initially in patients with AML and subsequently across multiple indications.

Favorable pharmacokinetics have been observed, including a half-life supporting once-a-day oral dosing, dose proportional C-max and a high volume of distribution suggesting broad entry into tissues.

Voruciclib: Inhibition of MYC

Dysregulation of MYC is associated with many cancers. CDK9 is a known regulator of MYC transcription and a modulator of MYC protein phosphorylation. Data reported at the American Association for Cancer Research (AACR) Annual Meeting 2021 in preclinical models demonstrates that voruciclib:

• Results in a rapid decrease in the phosphorylation of proteins that promote MYC transcription
• Rapidly decreases phosphorylation of MYC protein on Ser62, a site implicated in stabilizing MYC in KRAS mutant cancers
• Possesses single agent activity against multiple KRAS mutant cancer cell lines both in vitro and in vivo
• Synergistically inhibits KRAS G12C mutant cancer cell lines in combination with KRAS G12C inhibitors, both in vitro and in vivo

The research presented suggests that voruciclib could be an attractive therapeutic target for cancers driven by MYC overexpression such as those harboring KRAS mutations and warrants further investigation.

Clinical Program

In early clinical studies evaluating more than 70 patients with solid tumors in multiple Phase 1 studies, along with pre-clinical studies, suggests voruciclib’s ability to inhibit CDK9 at doses that appear generally well-tolerated to date in clinical studies.The ongoing development program is intended to further clarify the clinical dose and overall clinical profile of voruciclib, particularly for use in combination with other cancer therapies.

We are currently evaluating voruciclib as a single-agent and in combination with venetoclax in patients with AML and plan to expand clinical development into patients with B-cell malignancies. We are also continuing to evaluate the potential of voruciclib against cancers where MYC is dysregulated.

Voruciclib is being evaluated in patients with B-cell malignancies and AML. B-cell malignancies are a type of cancer that starts in B lymphocytes, a type of white blood cell. They include both slow growing (indolent) diseases as well as aggressive diseases and represent a collection of different blood cancers. Acute myeloid leukemia, or AML, is a cancer that starts in the bone marrow, where the body produces new blood cells. AML normally begins in cells that mature into while white blood cells, but can also start in cells that mature into red blood cells and platelets.

We are also considering the clinical evaluation of voruciclib in combination with other therapies in patients with solid tumors driven by MYC overexpression, such as those harboring KRAS mutations.