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Spanish Biotech Peptomyc Advances MYC Inhibitor in Pancreatic Cancer After Positive Early Data

Pancreas model

NEW YORK – Vall d'Hebron Institute of Oncology spinout Peptomyc is moving its investigational MYC inhibitor into a Phase Ib trial in advanced pancreatic cancer after an encouraging readout from a first-in-human study.

The Barcelona-based firm believes its agent, dubbed OMO-103, is the first pan-MYC inhibitor to show benefit in a Phase I trial, which is a significant feat since the target has historically been considered "undruggable," said Laura Soucek, Peptomyc CEO and head of VHIO's Anti-Tumor Therapy Modelling Group.

"MYC is a protein that continuously changes shape," Soucek said. "Small molecules have been the standard of care for years and years, and small molecules cannot recognize a protein that changes shape all the time."

Unlike the drugs used in past attempts to target MYC, Peptomyc's drug, OMO-103, is not a small molecule. "Instead, we used mini proteins, which have a much larger interaction surface," she said. As Soucek explained, the mini protein is designed to chop MYC into a shape that cannot change. Once MYC binds to OMO-103, it can no longer bind to DNA and therefore becomes inactive. At the same time, the firm's compound also occupies the DNA in the form of inactive protein complexes at binding sites. In this way, OMO-103 has "a double mechanism of action," Soucek said.

The mini protein consists of 91 amino acids, which have a unique ability to enter the cancer cell and penetrate its nucleus.

In the Phase I trial, the results from which were published in Nature Medicine last week, Peptomyc enrolled patients with any type of advanced solid cancer and regardless of MYC expression. The clinical trial, dubbed MYCure, included 22 patients with various types of advanced tumors including pancreatic, colorectal, ovarian, lung, and triple-negative breast cancers, and sarcoma. The patients all had received a median of four prior therapies.

"The safety profile of this drug is excellent," Soucek said of OMO-103's observed activity in the Phase I trial. Only one serious adverse event, an infusion-related reaction, was considered related to the agent.

In terms of efficacy, of 19 patients evaluable for response to OMO-103, 12 reached a predefined nine-week time for assessing the drug's anti-tumor activity, and eight out of those 12 patients had stable disease at that point. One patient with metastatic pancreatic cancer had a 49 percent reduction in total tumor volume. Investigators also used Guardant Health's Guardant360 liquid biopsy assay to measure changes in the levels of circulating tumor DNA across 73 genes. After 11 weeks on treatment, one of the patients — the individual with pancreatic cancer — had had an 83 percent reduction in ctDNA.

According to Soucek, these "pleasantly surprising" results are why the firm has now decided to further test OMO-103's activity specifically in pancreatic cancer patients. "We like challenges, obviously," she said. "There's, of course, a huge unmet need for metastatic pancreatic cancer patients."

Biomarker stratification plans

Unlike the first-in-human trial, into which Peptomyc enrolled all comers, Soucek said that this next trial will have a predictive biomarker built into its inclusion criteria. The biomarker is based on models identified using machine learning, she said. Additionally, while the original trial looked at OMO-103 monotherapy, the new trial is designed to evaluate OMO-103 combined with standard-of-care chemotherapy.

"There is no single molecule that by itself is predictive," Soucek said of the biomarker she and her team are evaluating in the pancreatic cancer trial. "It's a combination of them." The biomarker involves checking for the presence of antibodies, so-called soluble factors, in the blood.

Peptomyc has already begun enrolling patients into this next Phase Ib pancreatic cancer trial and completed the safety run-in portion with a lower dose of OMO-103. Soucek predicts the trial will wrap up within three years.

Next steps, future ambitions

The Phase Ib trial is currently taking place at four hospitals in Spain. Although the company has sufficient resources currently to only study the drug at European institutions, Soucek and her team are eager to expand testing to more sites outside of Europe. However, doing so will require additional fundraising efforts and potentially partnerships, she acknowledged. "The idea is to partner as soon as possible with a portfolio of different pharma companies," she said, adding that OMO-103 could be an ideal drug to combine with a range of existing agents.

"It makes sense biologically because MYC is a mechanism of resistance to most of the standard treatments, or even personalized medicines, that we find," she said. "Combining our MYC inhibitor with any of these treatments would give these other treatments better chances to be longer lasting and more effective. We can do better together and reach more oncological indications."

Soucek considers herself a researcher first and foremost, and as such, she noted that launching Peptomyc as a company was just the most efficient path to bringing OMO-103 to the clinic. Soucek and Cofounder Marie-Eve Beaulieu, also a researcher, spun out Peptomyc from VHIO in 2014. Beaulieu is now the company's CSO.

"We were two scientists founding a company, and although I assumed the role of CEO of a company and learned about business, I never left my lab," she said. Indeed, Soucek is still actively leading her lab at VHIO. "It's my pride," she said.

Going forward, Soucek said she hopes to explore OMO-103's efficacy in other indications beyond pancreatic cancer. "We have the duty to do that because the signal of clinical benefit was observed in our Phase I trial in multiple indications," she said. For instance, the results suggested a benefit in sarcoma, colorectal cancer, and salivary gland cancer, among other indications. The firm is planning for an investigator-initiated trial in pediatric cancer and is eyeing a combination treatment strategy with KRAS inhibitors in non-small cell lung cancer patients, too.

"These are the next on the list, and we have a wish list that encompasses many more products and indications, but for now, it's just a matter of resources," she said.

In December, Peptomyc and VHIO jointly received €4 million ($4.29 million) from the Spanish Ministry of Science and Innovation and the European Union's NextGenerationEU program to further develop OMO-103. The firm is using the funds to advance OMO-103 into the new trial as well as to explore the possibility of developing a new drug that can cross the blood-brain barrier and treat central nervous system tumors.

In the meantime, Soucek acknowledged that other MYC-targeting research efforts and early-stage candidates are beginning to enter the scene. "People are finally believing that we can drug MYC," she said. She believes her firm's approach is the most advanced and most promising, but rather than seeing the other efforts as competition, she looks forward to observing results from them as they come to fruition.

Companies trying to target MYC in various cancer types include Omega Therapeutics and Monte Rosa Therapeutics, among others.

"This has been a very challenging approach, and there's a lot of resistance in the field" likely due to the fact that until recently MYC was considered undruggable, she noted. "People always say that science is made of trailblazers … but we get pushback and skepticism all the time," she said. "We need to prove things five times before anyone even believes in a new approach. Scientists need to be more open-minded."