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Freenome Maintains CRC Early Detection Timeline as New Biomarker Discovery Studies Progress

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NEW YORK – Fresh off of a $270 million Series C financing round, multi-omics liquid biopsy firm Freenome said that it has expanded its ongoing colorectal cancer early detection trial, PREEMPT, by opening recruitment to any US individual meeting the trial criteria, regardless of their location.

Freenome CEO Gabriel Otte said that the move has allowed the company to maintain its timeline for completing the trial by the end of 2021, despite challenges posed by the COVID-19 pandemic, which has significantly reduced the number of routine colonoscopies being performed. This directly impacts the number of patients eligible for PREEMPT, which is prospectively analyzing blood samples taken at the time of colonoscopy in order to validate the ability of Freenome's test to identify early, non-symptomatic cancers and high-risk precancers.

The recently raised funds will help maintain the new expanded model for the trial, in which Otte said Freenome has onboarded a much larger number of sites and created a centralized pathology protocol and education system that helps it quickly add new ones.

This means that if patients wants to join the trial, regardless of their location, Freenome can either direct them to a convenient participating site, or, if one isn't available, rapidly bring an appropriate nearby facility into the fold.

"It was actually always our intention to launch this [but] it takes a significant amount of time, as you might imagine, to address all the concerns," Otte said. "That includes things like having centralized pathology, for example, so that all of our pathology reports are consistent and high quality. And it has to do with … making sure that the clinics know the right protocols, making sure that the people who are doing the blood collection are doing it the right way in the right tubes at the right time."

"We've captured ... a huge swath of the groups that are out there to be able to sort of execute on this. But we're also onboarding new sites all the time," he added.

With PREEMPT progressing apace, Freenome also said that the new funding will help it expand its early detection efforts beyond colorectal cancer and will support new exploratory work using its multi-omics and machine learning platform to search for novel precision oncology biomarkers.

Two recent conference presentations have offered a glimpse of the types of discoveries that Freenome is hoping to enable with these broader explorations.

In June the company presented a poster at the second online session of the American Association for Cancer Research's annual meeting. In collaboration with Novartis, Freenome researchers used the company's technology to investigate whether pre-surgery cell-free DNA and circulating proteins could predict progression in non-small cell lung cancer patients after surgery.

Finding predictive biomarkers for the adjuvant and neoadjuvant settings has become an area of increasing interest for late-stage, metastatic cancer.

Otte also argued the need to create personalized care strategies in earlier-stage disease will only become more and more pressing as early-detection technologies like Freenome's gain approval and enter the clinic over the next few years.

"I'm assuming that Freenome and other companies in the space, we're all going to be successful to a certain extent in getting our tests out. Having multiple early detection tests across multiple different cancer types will fundamentally change how we treat cancer," he said.

With about 80 percent of cancers currently diagnosed in advanced stages, therapies and diagnostics "have really been keyed toward late-stage cancer," he added. "All these tests are on the market are no longer going to hold when we systematically shift the distribution to mostly early-stage detection."

"We're going to need new adjuvant therapies and neoadjuvant therapies with their own companion diagnostics and with patient monitoring tests for early stage." New tools will have to emerge to make sure that this new generation of diagnostics is not just identifying patients and then leaving them hanging, Otte argued.

In their AACR study, Freenome and Novartis retrospectively analyzed pre-surgery plasma samples from a group of 24 patients with stage I to stage III NSCLC diagnosed in 2004 (16 whose disease progressed and 8 whose did not).

Investigators performed whole-genome sequencing of cell-free DNA, calculating a probability of gene activation based on cfDNA fragment length and transcription start site data. They also estimated transcription factor activity for 504 transcription factors by measuring binding site accessibility across the genome, and, in parallel, measured the abundance of approximately 450 proteins, including cytokines, receptors, and enzymes.

Using statistical methods, the researchers probed these tumor-derived and non-tumor-derived signals, hoping to identify factors that differentiated progressors from non-progressors.

According to the authors, the results revealed novel cfDNA associations that pointed to immunoregulatory pathways that could be linked to early-stage NSCLC progression. Lower IL-1RN gene activation was associated with more favorable progression-free survival, while a lower abundance of its gene product, IL-1RA protein, was associated with longer time to progression.

Taken together, the team wrote, the results support further evaluation of IL-1RN and IL-1RA as potential prognostic biomarkers for progression risk in early-stage lung cancers. These, and other findings, could also provide hints for new drug targets for early-stage patients.

Although Otte emphasized the potential Freenome sees in early-stage disease, the firm is also applying its platform for discovery in areas of unmet need in advanced cancer.

At this year's annual meeting of the American Society of Clinical Oncology, held online in May, the firm shared data from another lung cancer biomarker discovery study.

Working with researchers at the Institut Curie in Paris, investigators from the company used the Freenome platform to mine for biomarkers associated with response to the cancer immunotherapy nivolumab (Bristol-Myers Squibb's Opdivo) in patients with advanced NSCLC. More specifically, the study focused on the use of fragment size analysis of cfDNA to identify potential non-tumor-derived biomarkers, as opposed to focusing only on genomic alterations in circulating tumor DNA.

The group analyzed plasma taken at baseline, and then again during the eighth week of treatment, from stage IV NSCLC patients enrolled in the ALCINA clinical trial. Researchers performed whole-genome sequencing of extracted cell-free DNA and estimated the cellular origins of the resulting sequences based on an analysis of co-fragmentation patterns. As in the Novartis study, they also estimated transcription factor activity by measuring binding site accessibility.

After various statistical analyses, the authors concluded that baseline tumor fraction was not predictive of immunotherapy response, although, as would be expected, the change from baseline to week 8 was.

Interestingly, a higher level of monocytes at week 8 of therapy — as inferred by the cfDNA co-fragmentation data — was also associated with response, as well as with overall survival.

The authors argued that the results provide evidence that measuring just ctDNA as a surrogate for tumor fraction may be missing important other data that can be gleaned from cell-free DNA. Whether or not added information from the larger cfDNA fraction markedly improves prediction, being able to measure changes in the immune system, "as reflected by cellular composition and transcriptional activity inferred from cfDNA," might at the very least benefit biomarker discovery and drug target identification, they wrote.

According to Otte, future data will hopefully expand on additional ways Freenome's technology can provide insight into multi-factorial aspects of disease processes and patient prognosis, especially in early-stage disease.

In the meantime, the company believes PREEMPT will conclude within its planned timeline — by the end of next year.

As part of the FDA review process, the company is supplying the agency with interim data as the trial progresses, and Otte said that its usually about 9 to 12 months after a final submission that FDA furnishes an approval, assuming the trial results are positive and sufficient.

That said, "we don't know if it's going to take less time or a longer period of time," he added. "Right now, everything's taking significantly longer because the FDA's focus is on more urgent matters."