NextCure: A Biomarker Approach to Immuno-Oncology Therapeutics
NextCure is charging toward the end of the year with three immuno-oncology clinical trials and what they feel is a distinctly unique approach to using biomarkers to guide their drug-development process.
By Mark Terry | September 8, 2023
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As Beltsville, Md.-based NextCure heads into the final months of 2023, the immuno-oncology company expects to have data readouts on three separate clinical trials by the end of the year. Alina Barbu, PhD, Associate Director of Biomarkers and Stephanie Kordahi, Master of Science (MS) in Pharmaceutical Sciences, Drug Development, Director of Clinical Operations, took time to speak with BioBuzz about the company’s unique approach to developing these new drugs and how they hope it will be beneficial to cancer patients.
Currently, the company has three ongoing clinical trials. One is a Phase Ib/II study evaluating NC410 in combination with Merck’s checkpoint inhibitor Keytruda (pembrolizumab) in patients with immune checkpoint naïve or checkpoint refractory solid tumors that express a LAIR2 fusion biomarker. The drug is a first-in-class therapeutic designed to block immune suppression mediated by LAIR-1. LAIR-1 and LAIR-2 are immunomodulatory receptors expressed on T cells and myeloid cells, as well as dendritic cells.
A second Phase I trial is evaluating NC525 in acute myeloid leukemia (AML) patients. Dr. Barbu says, “NC410 and NC525 focus on the same receptor target, which is LAIR-1. The drugs use different mechanisms.”
LAIR-1 works on immune cells, such as T cells or NK cells, by having an inhibitory effect, practically turning that T cell off, says Dr. Barbu. “You don’t want to turn off T cells because they won’t exercise their immune effect on a tumor and kill it. So with NC410, we’re trying to stop the inhibition of an immune cell by mimicking the counterpart of the receptor, which is LAIR-2, which interferes with binding of LAIR-1 to its target.”
NC410 is an engineered compound that interferes with the binding of LAIR-1 with its target, which stops interfering with the inhibition of immune cells. “Basically,” Dr. Barbu says, “the purpose of the NC410 treatment is to activate the immune cells.”
The NC410 combination trial is targeting colorectal cancer, esophageal, endometrial, ovarian and head-and-neck cancers.
NC525 is targeting AML, with the intention of inhibiting AML stem cells. “Interestingly,” Dr. Barbu says, “LAIR-1 does not have an inhibitory effect on AML cells, it has an activation effect, a survival effect. This means that an AML stem cell that carries LAIR-1 will live better. You don’t want that. So we have two different approaches, but we are actually looking at the same target.”
The third study, a Phase I/2 trial, is evaluating NC762-01 in patients with solid tumors and high expression of a tumormarker dubbed B7-H4. B7-H4 promotes cancer tolerance and may in some cancers contribute to Treg cell development.
Kordahi says, “B7-H4 can be common in ovarian cancer patients and breast cancer patients. There are about seven or eight tumor types that highly express those biomarrkers. Since it is a Phase I study, we looked at all kinds of advanced metastatic tumors in the beginning. Now we’re focusing on enrolling more patients who are expected to have higher expression of B7-H4, like ovarian and breast cancer.”
An investigator-initiated trial is evaluating NC318, an Anti-Siglec-15 humanized monoclonal antibody alone and in combination with Merck’s Keytruda in pretreated non-small cell lung cancer patients. Yale Cancer Center investigators will present data from that study at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer in Singapore in September.
One of the unique aspects of NextCure’s approach to early clinical trials is live biomarker testing. The company is collected blood and tissue samples from the patients at screening but is also doing so throughout the course of their participation in the trial, almost in real-time.
Dr. Barbu notes, “At established time points, we collect samples from the patients which we will process immediately and will have the information as the patient follows up — two weeks, one month, two months, etc. As the patient moves and evolves through the treatment course, we can observe real immune changes, which is what we are interested in when we look at, for example, peripheral immune populations in patients. This allows us to establish immune evolution and the response of the patient during the trial.”
One of the philosophies underpinning this approach is that tumors fight back against the immune system, evolving to adapt to survive against treatments. The company’s Chief Medical Officer, Han Myint, MD, likes to say that tumors try everything they can to fool the immune system — change mutations, change biomarkers, change whatever they can so the next time the immune system or a drug tries to attack it, it can survive.
“Which is why treatment for cancer is so complex, why patients become refractory and resistant to medications. That’s why we have to keep doing what we do, and we have to be smarter than the tumor,” Kordahi says.
As a result, there are constant conversations between NextCure’s Biomarker Team, Clinical Team and the outside clinical sites. As they generate ongoing immune cell data, they can tweak the trial as they better understand how the immune system and cancer cells are evolving in the war against the disease. The company believes this information will be very useful as it moves on into Phase II and Phase III trials, which involve many more patients. With continued analysis of immune evolution and biomarkers, they believe it will power their future studies to better understand which patients and indications will best respond to the therapeutics and fine-tune their treatment protocols.
Dr. Barbu says, “I don’t think many companies do this, because it involves a lot of work, a lot of resources, and a lot of timing that must be gotten right. And it also involves a lot of patience.”
The company’s second-quarter financial report on August 3, 2023, indicated it expects a flood of data on the studies in the fourth quarter. It also is in a solid financial position, with about $131 million in cash which should be able to fund operations into mid-2025.
Kordahi says, “Right now, we’re mostly in solid tumors, but are moving into leukemia as well. We have other exciting things in the pipeline to potentially expand into other indications. At NextCure, we do all our own discovery, everything from R&D all the way through taking a drug into the clinic — we do it all here in-house. Recently we brought onboard our GLP lab, so we do that in-house as well. For a very small organization, I think we’re very mighty in that we really can take a drug from start to finish, from a concept to the patient pretty much within our organization.”
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Mark Terry is a freelance writer, editor, novelist and ghostwriter. He holds a degree in microbiology & public health and spent 18 years in infectious disease research and clinical and research genetics prior to his transition to a writing career. His areas of expertise include biotechnology, pharma, clinical diagnostics, and medical practice management. He has written literally thousands of articles, as well as market research reports, white papers, more than 20 books, and many other written materials. He currently lives in Michigan with his family.
