Bill Lundberg, MD., is president and chief executive officer of Merus, a clinical-stage oncology company developing bispecific and trispecific antibody therapeutics. Prior to joining Merus, Lundberg served as chief scientific officer of CRISPR Therapeutics, as head of translational medicine at Alexion Pharmaceuticals, and in leadership roles at other biopharmaceutical companies.
Lundberg recently spoke with Inside Precision Medicine’s editor in chief, Damian Doherty, about the company’s pipeline, including its most advanced cancer drug candidate, zenocutuzumab (Zeno), a bispecific antibody with a HER2/HER3 target combination; its first indication is directed at neuregulin (NRG1) fusions (NRG1+), rare and powerful drivers of cancer cell growth. Zeno has shown encouraging clinical activity in patients with NRG1+ cancer including lung, pancreatic, and other types of solid tumors.
Doherty: What are NRG1 fusions and what led Merus to target this mutation?
Lundberg: Gene fusions involving NRG1 are found in a subset of patients with many different tumor types, including pancreatic and non-small cell lung cancer (NSCLC). From the beginning of our work on NRG1 several years ago, the Merus team developed a deep knowledge into the science of NRG1 in cancer. We came to understand that these cancers are driven by the translocation of a strong promoter in front of the NRG1 gene; this leads to expression at very high levels of a membrane bound form localized proximate to HER3. The resulting NRG1 fusion protein binds HER3 which then combines with HER2; this results in a signal to the cell to grow and divide in a continuous, uncontrolled manner. NRG1 fusions have been reported in roughly 0.5% to 1.5% of all pancreatic cancer, and 0.3% to 3% of all non-small cell lung cancer. What’s interesting is that this particular alteration appears to occur in the absence of other so-called “driver” mutations–that is, mutations known to cause or drive the growth of cancer.
NRG1 fusions are associated with poor prognosis, low response to cancer therapy, and shorter survival, particularly in lung cancer. Currently available therapies are not particularly effective in patients with NRG1+ NSCLC and pancreatic cancer.
Any time where you clearly know the driver of cancer growth, are able to identify patients with this specific genetic change, and you have a drug that targets the specific genetic change that causes the cancer, you have a higher potential to develop a really meaningful drug for patients. We believe Zeno has a real opportunity to be a clinically meaningful drug, both first-in-class and best-in-class, for NRG1+ cancer.
Doherty: What excites you most about the Zeno clinical trial results?
Lundberg: We were very excited to see the interim clinical data on Zeno and NRG1 fusion cancer which we presented at the Amercan Society of Clinical Oncology annual meeting in June 2022. In our clinical studies, NRG1 fusions occurred in a wide range of different tumor types. Across all the different tumor types treated in our clinical trial, as of our last datacut in April 2022, the response rate to Zeno by investigator review was 34% in these patients whose cancer had progressed after previously receiving the standard therapies for their disease. In NRG1+ pancreatic cancer, the response rate was 42%, and in NRG1+ lung cancer, it was 35%. And 70% of patients in the clinical trial had some degree of tumor reduction. The responses appear durable, with the median duration of response more than nine months. This is substantially better than the historical comparators of what the patient could otherwise achieve after front line standard of care. In light of these results, we believe Zeno clearly has the potential to be clinically important.
Based on our clinical progress with Zeno, we’re moving towards regulatory filing to gain approval for use of Zeno for NRG1+ cancer. Beyond this, we believe that Zeno could help more patients in combination with other standard therapies in NRG1+ cancer. Recent scientific work also suggests potential for Zeno to be efficacious in a subset of cancers that don’t have NRG1 fusions. We’re planning to evaluating several hypotheses in clinical trials.
Doherty: Zeno has a unique mechanism of action that you call “dock and block.” How does it work?
Lundberg: One arm of the bispecific antibody Zeno binds, or “docks”, onto HER2. The other arm of Zeno binds to HER3, thereby “blocking” NRG1 from binding to HER3, while preventing HER3 from interacting with HER2. In this manner, Zeno is designed to directly address the problem of NRG1 fusions binding to HER3, but also goes one step further to block the next step in signaling which is the interaction of HER3 with HER2, shutting down any further intracellular signaling and preventing further oncogenic or cancerous growth. In fact, in pre-clinical studies, we’ve demonstrated that Zeno’s mechanism is more than 100 fold more potent than simply trying to block the HER3 protein with an anti-HER3 monoclonal antibody.
Doherty: How are you identifying patients with NRG1 cancers?
Lundberg: To identify patients for our eNRGy clinical trial, we established a global network of collaborations with industry and academic institutions for NRG1 fusion testing and genetic screening for cancer patients. Molecular testing panels should incorporate RNA-based testing as the most accurate method for NRG1 fusions to identify patients who may benefit from Zeno. DNA-based next-generation sequencing (NGS) can detect NRG1 fusions but at a much lower sensitivity than RNA-based NGS. There are large intronic regions in the NRG1 gene which are not typically sequenced by DNA-based NGS methods such as whole exome sequencing. Also, some NRG1 fusions may not result in gene expression of a functional transcript with oncogenic properties, which can result in DNA identifying non-functional fusions. For NRG1 fusions, RNA-based NGS is the most effective detection method, and we have invested in creating partnerships and funding RNA testing to enable more patients to be screened to determine if they have NRG1+ cancer.
As we continue to advance Zeno, education about the importance of RNA-based molecular screening is a priority. This type of screening is not only beneficial for those with NRG1+ cancer; a better understanding of the underlying drivers of cancer can help guide treatment and clinical trial opportunities across the population of patients.
Doherty: How are your bispecifics, which are called “Biclonics®”, different from others?
Lundberg: Biclonics is named for our technology of Bispecific Common Light chain antibodies made from monoclonal cells. Biclonics® are our prioprietary bispecific antibodies—binding to two different targets—in the shape of a fully human IgG antibody. In the early days, therapeutics designed to bind mulitple targets were Frankenstein-like structures, where pieces of a protein or an antibody would be stuck together. The result was structures that were hard to work with, hard to produce in the quantities needed for clinical trials, and not surprisingly, immunogenic in patients. The industry then moved towards more antibody-like structures, but these can also be challenging to produce with two different heavy chains and two different light chains. When you put all those genetic elements in a cell to produce a bispecific antibody, they can mix and match many different ways—how do you ensure that the particular combination of heavy and light chains produced by the cell is the one that you want?
At Merus, our Biclonics are made as monoclonal antibodies, each cell producing only essentially one unique type of antibody. You get a pure product, which by the way is where Merus derives its name—which means “pure” in Greek.
This resulting product can only be achieved with our unique proprietary common light chain technology and charge-based pairing. Out of a single cell, we can essentially produce a fully human IgG1 monoclonal antibody which binds two different targets. We can also produce Triclonics which can bind three targets at once. Because our Biclonics and Triclonics are monoclonal antibodies, with only one type of multispecific antibody coming out of each cell, we can employ all the tools and technologies of monoclonal antibody discovery, development, and engineering. We can screen of hundreds or thousands of antibodies to choose the combinations that are the most effective in a variety of assays for bringing into the clinic. In addition, our Biclonics have been observed in our clinical trials to have predictable in vivo behavior, a consistent, durable half life, and importantly, have generally been well tolerated in patients.
This approach gives us a significant advantage in two ways. We start off in the clinic with a candidate medicine that has been selected empirically from hundreds or thousands of molecules, based on the biology and other characteristics in multiple orthogonal assays. Additionally, because it’s a fully human IgG1 antibody, it has the potential to be much more robust as a drug, in terms of production, drug-like properties, potential activity and safety for patients.
Doherty: In addition to Zeno, what other drug candidates is Merus advancing?
Lundberg: We have four clinical stage candidates, including Zeno, all of which came from our proprietary technology platform. The progress we’ve made with our portfolio of our drug candidates, along with those developed for partners like Incyte and Loxo, has validated Merus’ platform technology as being robust and having a potential to make meaningful cancer medicines. It is incredibly important and exciting for us to have an engine for developing innovative therapies and advancing them for patients. In addition to Zeno, we have petosemtamab which is a bispecific antibody that targets the well-established cancer target EGFR with one arm and LGR5, a cancer stem cell target in the WNT pathway, with the other arm. Other candidates in our pipeline are MCLA-129, which is a bispecific targeting EGFR and c-MET, and MCLA-145, a bispecific T-cell engager that binds CD137 and PD-L1.
We believe Zeno is only the beginning. We’re also making progress advancing these other drug candidates in the clinic, and in doing so, we are starting to deliver on our promise of closing in on cancer.
Damian Doherty has been in media and publishing for nearly 30 years, beginning in the early nineties at News Corporation. Damian has managed, edited, and launched life science titles in drug discovery and precision medicine. He was features editor of Drug Discovery World for fourteen years and founded, established, and edited the Journal of Precision Medicine in 2014. In parallel, Damian founded and organized the Precision Medicine Leaders’ Summit, a global, immersive 3-day senior leadership conference that still runs today. He edited AIMed magazine in 2019 before launching Photo51Media, a platform for illuminating untold, compelling stories in precision healthcare. Damian joined Mary Ann Liebert in 2021 to help steer the new rebrand and relaunch of Clinical OMICS to Inside Precision Medicine.