ENB-003 with Keytruda Shows Promise Against Advanced Solid Tumors

ENB-003 with Keytruda Shows Promise Against Advanced Solid Tumors
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ENB Therapeutics’ lead novel anti-cancer therapy, ENB-003, was found to be safe and showed promising anti-tumor activity, when given in combination with Keytruda (pembrolizumab), to adults with different types of advanced solid malignancies, including ovarian cancer and melanoma.

These are the early findings of an open-label Phase 1/2 trial (NCT04205227) that has recently finished dosing the third group of patients participating in its dose-escalation phase.

“We are very excited to observe the continued safety of our combination regimen as well as early efficacy signals as we escalate the dose into the expected therapeutic window of ENB-003,” Sumayah Jamal, MD, PhD, president, co-founder, and chief scientific officer of ENB Therapeutics, said in a press release.

Trial data was presented by the company in a late-breaking presentation, titled “Phase 1/2 study using ENB-003, a first-in-class selective ETBRi, in combination with pembrolizumab in subjects with advanced refractory solid tumors,” at the Society for Immunotherapy of Cancer’s 2020 annual meeting, held online, Nov. 11–14.

ENB-003 is a selective small molecule inhibitor of the endothelin B receptor (ETBR), a protein receptor that is overproduced in more than 40% of all cancer types and known to prevent immune T-cells from infiltrating into tumors and destroying malignant cancer cells.

By blocking the activity of this receptor, ENB-003 may restore the ability of immune cells to enter tumor tissues and reduce cancer resistance to other immunotherapies, like Keytruda, that work by boosting the immune system’s ability to see cancer cells as targets for destruction.

A Phase 1/2 trial is assessing the safety, tolerability, and efficacy of ENB-003 in combination with Keytruda as a treatment for adults with certain types of cancer, including melanoma, pancreatic, and ovarian cancer, which usually contain high levels of ETBR.

The study is divided into two parts. In an initial dose-escalation phase, participants will receive five increasing doses of ENB-003 (150, 300, 500, 750, and 1000 micrograms) in combination with a fixed dose of Keytruda, to assess the combination’s safety and tolerability, and to determine the optimal dose that will be used in the second part of the study. Before receiving the combination therapy in this phase, all patients will first complete a seven-day run-in period, where they will be treated with ENB-003 alone.

The second dose-expansion phase will focus on the efficacy of the combination therapy in patients whose tumors either failed or are highly resistant to Keytruda, including those with platinum-resistant ovarian cancer, refractory pancreatic cancer, and metastatic melanoma. The main goal of this phase is to assess if ENB-003 increases the responsiveness of tumors to Keytruda.

The three initial doses of ENB-003 administered to date in the study have been found safe and well-tolerated.

The combination therapy also showed early promising anti-tumor activity. From the nine patients treated in the study so far, four saw their disease stabilize and one with platinum-refractory ovarian cancer achieved a partial response (partial cancer elimination).

In this patient, tumor burden dropped by approximately 72% and no signs of disease worsening were seen after six months of treatment. This is particularly meaningful, considering that patients with recurrent ovarian cancer treated with Keytruda alone tend to live a median of 2.3 months without worsening, Jamal said.

“We are hoping for continued positive responses as we advance the trial and escalate the dose of ENB-003,” she added.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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