Under the Microscope: ENB Therapeutics
Why Avestria Invested in this Small Molecule Therapeutics Startup
In this series, we explain why we invested in our current portfolio companies. In the process, we hope to highlight the white spaces in women’s health and the life sciences — as well as the people, products, and companies working to fill those gaps. The name “Under the Microscope” refers both to our extensive due diligence process and our investment focus on healthcare and the life sciences.
In August 2015, former U.S president Jimmy Carter announced that his cancer (melanoma) had spread to his lungs and to his brain. However, in December 2015, he found that his tumors were gone.
During the few months in between, the former president was treated with a combination of radiation and immunotherapy. Immunotherapy — the process of triggering the body’s own immune responses to fight infection — is a relatively new cancer treatment that has had promising results against otherwise untreatable advanced or metastasized cancers, like Jimmy Carter’s. As of 2020, estimates show that 43.6% of the U.S cancer patient population qualifies for Immune Checkpoint Inhibitors (known as ICP inhibitors): a specific type of immunotherapy. A few years prior, the 2018 Nobel Prize in Medicine even went to James P. Allison and Tasuku Honjo for their work in advancing this field of treatment; they stimulated the immune system’s existing ability to find, recognize, attack, and kill tumor cells.
Allison specifically found a protein that could disengage the “brake” on T-cells, which, alongside B-cells, make up tumor-infiltrating lymphocytes (TILs). TILs are white blood cells that fight off infections by helping the body recognize cells that shouldn’t be present — like cancerous cells or groups of cancerous cells that have formed tumors — and killing them. Without the “brake”, Allison noted, T-cells wouldn’t be restricted.
Increased T-cell counts has shown to lead to better patient prognosis. The flipside, though, is that fewer T-cells can lead to adverse patient outcomes, and certain biological processes can deplete T-cells and lead to this shortage. One example is the overexpression of — or the production of too much protein by — a protein receptor known as the Endothelin Type B Receptor (ETBR). The ETBR takes part of its name from endothelin cells, which line blood vessels, lymph vessels, and the heart. They help clot blood, keep toxins out of tissues, and produce peptide hormones, such as ET-1, which, in turn, has two receptors: the ETBR and the Endothelin Type A Receptor (ETAR).
Although research linking the overexpression of the ETBR with cancers has been more limited than that into the ETAR’s role, the ETBR nonetheless offers a novel pathway for cancer immunotherapies. After all, blockading the ETBR, or preventing it from overexpression, has been shown to increase T-cell homing to tumors and help destroy them. In contrast, when the ETBR is overexpressed without any regulation, it prevents T-cells and, subsequently, the TIL from recognizing and infiltrating tumors, shortening patients’ expected lifespan.
Tumors that have few or no T-cells fighting them are called “cold tumors”. (A “hot tumor” has T-cells). Cold tumors are present in ovarian and pancreatic cancers among others. They also are “a major factor involved in initial resistance to ICP inhibitors”, including anti-PD-1 cancer therapies, which are a front-line immunotherapy treatment for multiple types of cancer. Because of this “resistance”, the effectiveness of ICP inhibitors is only about 15 to 20% for patients with cold tumors.
In other words, if allowed to go unchecked, an overexpressed ETBR prevents T-cells from finding and killing cancer cells, and this lack of T-cells can limit the effectiveness of a common treatment option, especially for advanced cancers.
ENB Therapeutics is offering a novel approach to cancer immunotherapy, developing the first-in-class ETBR antagonist to reduce the overexpression of the ETBR and the subsequent adverse results to patients.
ENB’s first product, ENB-003, is a small molecule drug that aims to increase the response rate and the clinical benefit for melanoma, ovarian, and pancreatic cancer patients who otherwise may not have a successful treatment option available. When combined with a specific type of ICP inhibitor — an anti-PD-1 — ENB-003 hopes to have a threefold effect: help stimulate the T-cells and their cancer-finding and -fighting ability, use the T-cells to turn cold tumors into hot tumors to overcome the tumor’s original resistance to ICP inhibitors, and, finally, create new lymph nodes that contain cancer-fighting T-cells and B-cells.
In short, the goal of ENB-003, when combined with anti-PD-1 therapies, is to increase both the effective rate of immunotherapy treatments and the number of T-cells and B-cells in the body to fight cancers in the first place.
Over the past few years, ENB’s Investigational New Drug Application was approved, allowing it to start dosing human subjects; the company has received Orphan Drug Designation for treating both melanoma and pancreatic cancers; and ENB is currently partnering with Merck to complete clinical trials pairing ENB-003 with the anti-PD-1 drug KEYTRUDA® (the same drug that former president Carter took). In 2021, the company reported the early results of its Phase I clinical trial, including a partial response in a ovarian cancer patient who had a ~95% reduction in her tumor and no disease progression after twelve months of therapy.
In 2008, research into the ETBR led to the conclusion that “these findings highlight a molecular mechanism with the potential to be pharmacologically manipulated to enhance the efficacy of tumor immunotherapy in humans.” We invested in ENB Therapeutics because we believe that it is capitalizing on the relatively recent research into and the success of immunology to “enhance” this treatment’s efficacy. In the process, ENB is on the path to create a novel and much-needed product for cancer patients who might not otherwise have an effective treatment option available. Through ENB-003 and ENB’s future products, we hope that more and more cancer patients will be able to see the same type of success as former president Jimmy Carter did when he first turned to immunology to help treat his own cancer in 2015.
At Avestria Ventures, we look for early-stage women’s health and female-led life science companies with products or technologies that improve healthcare quality and/or access, lower costs, induce clinical or behavioral change, are evidence based, have scalable commercialization plans, and have a sustainable competitive advantage. Know one? Contact us via our website, LinkedIn, or Twitter.
