This article was updated to correct the details of the ALPHA3 trial.
NEW YORK – Foresight Diagnostics is scaling up its R&D and preparing to initiate several prospective clinical trials aimed at showing the clinical utility of its minimal residual disease (MRD) assay.
The Boulder, Colorado-based company is engaged in one clinical study and plans to launch several more geared toward guideline inclusion over the course of the year.
"The last three years have really been about a lot of data generation," said David Kurtz, cofounder of Foresight.
Fellow cofounder and CEO Jake Chabon added that the firm has generated a considerable amount of data related to lymphoma in particular, largely from retrospective studies, and now plans to move into more prospective clinical trials.
Foresight recently partnered with Allogene Therapeutics to conduct the Phase II ALPHA3 trial that will test Foresight's circulating tumor DNA (ctDNA) MRD assay in improving outcomes through earlier relapse detection for patients with relapsed or refractory large B-cell lymphomas. That trial is expected to begin this summer.
Although Chabon said that it is too early to disclose many specifics, "we have active research partnerships with both biopharma and academic collaborators to generate evidence as to the performance and potential clinical utility of the test in different solid tumor indications."
The company is currently in the process of reviewing and selecting proposals for investigator-initiated studies to evaluate the clinical utility of MRD testing for B-cell malignancies as well as other indications. Foresight anticipates being able to launch one or two more prospective trials by the end of the year.
ALPHA3 and the other clinical trials that Foresight is evaluating are part of a broader push to grow the company.
Following a $58.8 million Series B financing round last year, the company moved from its previous headquarters in Aurora, Colorado, into a new lab facility in Boulder. The larger space supports a greater degree of automation and Foresight's strategy of using a streamlined central lab for developing and distributing kitted solutions, as well as supporting regulatory applications.
Since moving in, Chabon said, the company has invested heavily in automating its end-to-end workflow to make Foresight's operations more scalable and robust, particularly with respect to running clinical trials.
"There's a lot of operational infrastructure required to support real-time reporting," he said.
"We think that we can support the regulatory framework to run trials like ALPHA3 and [others] from within this lab," Kurtz added.
The central lab format, Chabon explained, is also what the company sees as the fastest way to eventually develop kits and get them into the hands of physicians, where they can begin informing treatment. Although kit production remains a ways off, given the need to first obtain regulatory approval, Chabon said that they are on the company's long-term "roadmap."
Chabon commented that Foresight is discussing the possibility of distribution partnerships to expand the company's reach throughout and beyond the US. However, he said, "right now, our focus [is] on the centralized model."
Foresight's MRD technology is driven by a method called PhasED-seq, which stands for Phased Variant Enrichment & Detection Sequencing, and is licensed to the company by Stanford University, where both Kurtz and Chabon worked as scientists.
PhasED-seq harnesses the improbability of two or more mutations occurring on the same ctDNA fragment as a means of boosting sensitivity while reducing sequencing errors.
Prior studies assessing the use of PhasED-seq in MRD detection have demonstrated an ability to detect one in 10 million cfDNA molecules with a low background error rate.
Reducing error rates by detecting two concordant mutational events makes PhasED-seq similar to duplex sequencing. Where duplex sequencing looks at two complementary strands of DNA, however, PhasED-seq interrogates target mutations on the same strand, regardless of whether the complementary strand is present.
Mark Murakami, an assistant professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute who specializes in leukemia and lymphoma genomics and experimental therapeutics, commented that while existing targeted panel assays are generally sufficient for tumors with high mutational burdens, the typically lower burdens found in tumors such as follicular lymphoma and mantle cell lymphoma cap the sensitivity of residual disease monitoring when considering only pathogenic mutations.
"The ability to predict relapse is critical in some of these lymphomas, since they often affect older individuals, who are the most prone to experience treatment-related adverse events," he said via email. "A maximally sensitive assay for MRD could potentially guide efforts to modulate the intensity of post-induction therapy and focus aggressive treatment and its attendant toxicities on those patients who stand most to benefit."
Given PhasED-seq's proven sensitivity, Murakami said that it has potential to become a commercial MRD assay. He noted, however, that certain treatment modalities where MRD testing might be most informative are still being investigated for their clinical utility as compared to standard-of-care treatments. These include decisions about post-induction therapeutic de-escalation or forgoing interventions such as consolidative autologous transplant, which is sometimes performed for mantle cell lymphoma.
"Until such an approach achieves regulatory approval, reimbursement will be challenging," he said, "particularly since the commercial implementation of PhasED-seq is quite expensive."
Kurtz and Chabon acknowledged that because these clinical concepts remain in development, the road to commercialization and reimbursement is longer.
"But because our main goal is to improve patient outcomes in the long term, that's a road we're committed to," Kurtz said. "We look at the landscape of diagnostic tests, and the ones that stick around for the long term are the ones that have a meaningful impact on patient care and outcomes."
Chabon added that with respect to future clinical trials, Foresight is focusing on those that write MRD into the trial protocol as a means to inform treatment decisions.
"We really want to build a robust dataset of evidence as to why the test should be used to inform clinical decision-making, and that will inform our reimbursement strategy and also guideline [inclusion]," he said.
Foresight anticipates that the results of ALPHA3 will help move PhasED-seq and ctDNA-based MRD detection toward guideline inclusion. In that study, patient outcomes will be compared to the results of both ctDNA MRD and PET/CT scans, which are the current standard of care in DLBCL disease monitoring.
"PET/CT scans are fraught with false positives and false negatives," Kurtz said. "There's a growing recognition that just having metabolic activity on a CT scan does not mean you have disease. Circulating tumor DNA MRD can improve on PET/CT scans [and] in my mind, that's the first potential way to foray towards guideline inclusion."
Foresight is also evaluating adding MRD to progression-free survival (PFS) as a clinical trial endpoint. This "modified" PFS, Kurtz explained, may improve trial efficiency and help speed therapies to market.
"Progression-free survival … has the same limitations that PET scans have," he said, in that absence of apparent progression doesn't mean that the disease isn't still there.
Adding MRD measurements to PFS, he argued, could allow clinical trial results to be read out much faster.
Given the "astronomical" timelines and costs of drug development, Kurtz continued, any effective method for speeding up trial readouts could translate to significant savings in terms of both time and money, something the company thinks will make its technology attractive to investors.
Chabon said that while Foresight is in a "strong" financial position right now, the company continues to attract investors and is actively discussing potential strategic partnerships.
"The investor community has generally been positive [about] the progress we've been making and the data we've been generating," he said.
In the meantime, the company is also defending its intellectual property in a patent infringement case levied against it by Personalis, which first sued Foresight in 2022, alleging that it infringed on three patents related to Personalis' whole-genome-enabled, tumor-informed MRD test. Personalis filed a second patent infringement lawsuit last year, focusing on three more MRD-related patents.
Chabon said, however, that the litigation "is not impacting our ability to move our products forward … or to deliver on these trials."