This story has been updated to include additional information from Delve Bio.
NEW YORK – Delve Bio, a star-studded startup that launched earlier this summer, is seeking to jumpstart unbiased, metagenomic sequencing-based infectious disease testing.
The firm will begin by improving a test that was developed by University of California, San Francisco researchers to detect pathogen DNA and RNA in cerebrospinal fluid, with a primary goal of cutting turnaround time and moving the test forward in the diagnostic order of operations. From there, Delve will look to expand into other indications, with eyes on the prize of respiratory pathogen testing.
"Right now, we're last in line," after traditional pathology methods and both pathogen-specific and panel PCR tests, said Brad Murray, CEO and cofounder of Delve. "It's about moving from being a test of last resort to moving to be the test where there's some sort of trade-off and it makes sense."
The test, Delve Neuro, is a rebrand and refresh of the UCSF test developed by the lab of Charles Chiu, also a cofounder. The metagenomics-based approach, where available nucleic acids are sequenced and matched to databases, can provide answers when all other tests have turned up negative, In addition to bringing turnaround time down to about 60 hours from between 7 to 10 days, Delve is working on tweaking the molecular biology and informatics. Murray said the firm plans to expand sales primarily in the US by building its own clinical lab in Boston. "If we can get to 5,000 tests per year, that would be great," Murray said. The UCSF lab ran about 2,000 tests per year. "That's without a single dime of marketing and no customer support," he said.
Improving turnaround will "greatly improve the test's ability to impact clinical outcomes," and help gather data that could be used to prove clinical utility, said Kevin Messacar, a professor of pediatrics at the University of Colorado Anschutz School of Medicine and a consulting physician at Children's Hospital Colorado. He has collaborated with Chiu for years on the development, validation, and clinical utility of the test. "The quicker an answer comes back, the quicker we can modify antimicrobials," he said.
In addition to clinical utility, the startup will have to navigate issues of regulatory strategy, sequencing technology, and additional sample inputs and clinical indications.
Based in San Francisco, Delve came out of stealth in June after beginning operations in January. The firm has obtained $35 million in Series A financing and has 17 employees. According to Murray, the company's cofounders — who also include Joe DeRisi, president of the Chan Zuckerberg Biohub, Pardis Sabeti of Harvard University and the Broad Institute, Michael Wilson of UCSF, and Matthew Meyerson of the Dana-Farber Cancer Institute — spent most of 2022 plotting strategy and obtaining an exclusive license to the UCSF platform technology.
In 2020, Chiu and DeRisi published a paper in Nature Medicine, suggesting that the method detects bacteria with 79 percent sensitivity and 91 percent specificity and fungi with 91 percent sensitivity and 89 percent specificity using Illumina sequencing. The paper also reported data using Oxford Nanopore Technologies MinIon platform: sensitivity and specificity of 75 percent and 81 percent for bacteria and 91 percent and 100 percent for fungi, respectively.
Delve will run its tests on Illumina sequencing; however, Murray said the firm is also interested in other next-generation sequencing platforms. "We're sequencing 5X more deeply," he said, noting that the increase to 25 million reads was enabled by falling costs. "When first designed, it was 5 million reads per library. That's what they could afford to sequence."
That should improve sensitivity and specificity, but by how much is not clear. "We don't have absolute numbers on that yet," he said.
The biggest improvements to assay specs will be turnaround time. UCSF runs batches of samples once a week, Murray said, while Delve plans to implement variable batch sizing to run the test every day except Sunday. Bioinformatics analysis time has also been optimized to under an hour, or a decrease of 80 percent, he said.
One thing that likely won't be coming down is the price. UCSF currently offers the test for $2,900 and Delve is unlikely to change that at this time, Murray said. However, the firm is doing an economics and outcomes analysis that will help determine its pricing.
While turnaround time is falling, unless Delve makes a move to nanopore sequencing, its test will likely never approach the time scale of multiplex PCR assays, currently the second-line test after cell counts and gram staining, which take around one to two hours. "In a critically ill patient, 72 hours is a long time," Messacar said.
That means it will be limited to cases when those assays haven't detected common pathogens. Still, that's potentially an improvement upon being used as a test of last resort.
Faster turnaround time should help the test get ordered more, which could in turn provide data on how it could improve patient outcomes. That's especially important for doctors like Messacar, who are pushing the concept of diagnostic stewardship. At Colorado Children's, tests like the one Delve offers are only indicated in specific circumstances and require a consultation from an infectious disease expert and approval. Most times it is recommended, and it is approved, he said, although he did not have data on how often it is ordered. "It is not a common test for us to send," he said.
Delve will enter the neurological infection market with hundreds of existing customers from UCSF, which it plans to keep by offering more service than before, including providing sample collection kits. "If you are a customer and you want to interact with us, you'll get the right stakeholder" — potentially even the firm's executive suite — "on the phone with you in a week, max," Murray said.
The firm is not looking to sell kits but to run samples at a new CLIA lab. The test has US Food and Drug Administration breakthrough device designation, Murray said, but whether to pursue that with the agency is a strategic decision he'll have to make.
The other big strategic decision to make is which other clinical indications to pursue. "Neuro is a nice starting point because it's a severely unmet need, but it's a relatively modest market," Murray said. In addition to CSF, Delve has acquired IP covering plasma-based testing.
The "big prize" is respiratory pathogen testing, where about 400,000 patients end up in the intensive care unit per year in the US, excluding cases due to COVID-19. But post-joint surgery hospital readmissions — about 500,000 patients per year — and eye infections are also potentially big markets in terms of sample volume and are similar to cerebrospinal fluid in that there are fewer commensal microbes, making it easier to identify the infectious agent.
Taking a step back, Messacar suggested that metagenomic sequencing tests and other unbiased assays, such as the research-use VirScan assay for pathogen antibodies will eventually need to prove their worth with data from studies in clinical situations.
"When you have a test that can look for everything at once, it's hard to know which clinical situations it's going to have impact in," he said. "[The tests] go through rigorous validation; however, they're not required to show indication-specific clinical and financial outcomes, as a drug would."
That said, just one test result can have a large effect. "When an unbiased technology can detect an unsuspected pathogen and save a patient's life, it's very impactful in the way you think about them and their use," he said. "We just need to get more data and use tests in these cases in a cost-effective way."