The first clinical trial resulting from a new Zenith Epigenetic collaboration with the National Cancer Institute (NCI) will soon test a combination of the investigational therapy ZEN-3694 plus the immune checkpoint inhibitors Opdivo (nivolumab) and Yervoy (ipilimumab) for the treatment of resistant ovarian cancer.
The new partnership was developed to test ZEN-3694 across several cancer indications. For this upcoming study, the NCI also is collaborating with Bristol Myers Squibb, the developer of Opdivo and Yervoy.
“This collaboration will significantly supplement our efforts in expanding the portfolio of indications for ZEN-3694 both as a single agent and as a component of novel combination regimens with other therapies,” Donald McCaffrey, the president and the CEO of Zenith, said in a press release.
“NCI’s interest validates our belief that ZEN-3694 is a leading and differentiated BET inhibitor,” McCaffrey added.
ZEN-3694 is an orally administered small inhibitor of the BET proteins, which regulate the production of genes that are needed for the survival and excessive proliferation of cancer cells.
Over the last years, scientists have been testing BET inhibitors as a means to treat a broad range of cancers. While limited anti-cancer activity is observed when used as single agents, these inhibitors have shown promising effects in combination therapies.
BET inhibitors also seem to prevent resistance to various cancer treatments, according to Zenith. The company’s compound, ZEN-3694, was found to restore sensitivity to prostate cancer therapies that target the androgen receptor. It also was shown to increase the sensitivity of breast cancer patients without BRCA mutations to a new class of therapies called PARP inhibitors.
“Our therapy has proven to be safe and effective in prostate and breast cancer treatment and is combinable with multiple targeted agents,” McCaffrey said.
While combination trials for prostate (NCT04471974) and breast cancer (NCT03901469) are already underway, the recently established cooperative research and development agreement (CRADA) between the NCI and Zenith is expanding ZEN-3694’s clinical development to ovarian cancer and additional cancer indications.
This first collaborative trial aims to explore ZEN-3694 plus the immune checkpoint inhibitors, Opdivo and Yervoy, in resistant ovarian cancers.
Immune checkpoint inhibitors are medicines that block mechanisms used by cancer cells to evade immune system attack. Opdivo targets the PD-1 protein on cancer cells while Yervoy targets the CTLA-4 protein on T-cells — immune cells involved in the fight against cancer.
When used together, their effects are thought to be amplified, as Yervoy can promote the activation and formation of new T-cells, including memory T-cells, while Opdivo can help existing T-cells find the tumor.
This immunotherapy combination has shown promising efficacy in people with persistent or recurrent ovarian cancer. In earlier trials, more than double the number of patients achieved treatment responses with the combo than with Opdivo alone. The combo therapy also reduced the risk of disease progression or death by nearly half.
“This significant research and development agreement allows us to leverage the combined resources of the NCI, Zenith, and other pharmaceutical companies to develop ZEN-3694 in multiple oncology indications with significant unmet need,” McCaffrey said.
Zenith and the NCI expect to announce other clinical trials in the upcoming months, “based on the high level of interest from leading key opinion leaders and clinical researchers,” added McCaffrey.