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Bionano Genomics Expecting Clinical Validation Studies to Drive Platform Adoption

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NEW YORK – Bionano Genomics' optical mapping technology is seeing increased adoption by clinically oriented labs, especially in Europe, fueling hopes that the firm can emerge from a rocky 12-month stretch that has only been made worse by the COVID-19 pandemic.

With key clinical validation studies nearing publication in peer-reviewed journals, company officials strongly believe their Saphyr platform is well-positioned to be the do-it-all replacement for multiple cytogenetics technologies, including fluorescent in situ hybridization, chromosomal microarrays, and karyotyping.

Two Europe-based studies have already been posted to BioRxiv, showing near complete concordance with standard-of-care methods for diagnosing hematological malignancies and constitutional chromosomal aberrations. A third, from a US consortium led by Columbia University researcher Brynn Levy, is also nearing publication.

"We're getting to a critical mass in developing a body of literature that supports the Saphyr system in a variety of areas," Bionano CEO Erik Holmlin said. Other papers that have come out in 2020 include a study of DiGeorge syndrome, genetic heterogeneity in metastatic lung cancer, and bat genomes

The firm has patiently awaited those study results, as part of its go-to-market plan. Already, it is landing instruments in key European labs, some of which plan to develop laboratory-based tests run on Saphyr.

In 2020, Bionano has announced placements at the Curie Institute in Paris, NHS Lothian in Scotland, and MVZ Martinsried in Munich.  

In the US, the University of Iowa and PerkinElmer Genomics have adopted Saphyr with the intention of running fascioscapulohumeral muscular dystrophy (FSHD) testing on it. Georgia's Augusta University has adopted Saphyr with the intent of developing a pan-cancer diagnostic. And BioReference Laboratories subsidiary GeneDx and the Medical College of Wisconsin have both adopted Saphyr for clinical cytogenetic applications.

South Korea's Yonsei University Hospital has also picked up Saphyr, Holmlin said.

On a conference call with investors last week, following the release of the firm's second quarter financial results, Holmlin said that despite a severe, albeit predictable, drop in revenues compared to the prior-year period, the firm performed well in placing instruments and in consumables utilization rates. The Saphyr installed base grew to 89, with another 19 awaiting installation, including six placements in the quarter, compared to eight placements in Q2 2019. Consumables sold on a per-sample basis were up 189 percent, compared to the prior year period, he said, noting that the firm sold 1,421 flowcells compared to 490 a year ago. To further drive placements, Bionano has launched a new path to acquiring a Saphyr with a reagent lease model, which lowers the barrier to adoption and aligns with practices common to the clinical testing industry.

"So these are exciting results and we're very pleased with them and we believe that it reflects significant momentum even in a relatively tough quarter around the world," Holmlin told investors. 

That's not to say it will be all clear skies ahead for Bionano. "Around key financial parameters such as revenues, the situation has been really tough," Holmlin said in an interview. The pandemic's impact on business has just been the latest turbulence for Bionano, which in the past 12 months has seen multiple executives and board members depart, undergone an organizational restructuring, fallen out of compliance with a loan agreement, and has twice received noncompliance warnings from the Nasdaq stock market regarding listing requirements. Additionally, the firm received about $1.8 million through the CARES Act paycheck protection program, and several executives, including Holmlin, temporarily took 50 percent pay cuts.

But so far Bionano has managed to deal with all its tribulations. "I'm a first-time public company CEO, so all of them are new to me, but in the grand scheme of things they're not new," Holmlin said. "We have legal advisors that help us manage through it… nothing that we're doing is particularly new."

And he's been able to continue to raise money from the markets. The firm priced $18 million stock offerings in October 2019 and in April. Holmlin noted that since the end of the second quarter, the firm has received approximately $14 million from the exercise of warrants to purchase shares. The firm also announced on Monday an at-the-market equity program under which it may sell shares worth up to $40 million.

Meantime, Bionano continues to release new products, including new sample preparation kits to extract DNA from solid tumors and animal samples and bone marrow, respectively.

Optical resolution

Bionano launched Saphyr in February 2017 and went public in 2018. The optical genome mapping technology is a way to provide data on genomic structure, especially structural variants including translocations, indels, and inversions, among others. The technology is not a replacement for next-generation sequencing and is limited in resolution to about 500 bp.

Research uses for the platform include de novo assembly and structural variant analysis. Recent highlights for the firm on this front include use of Saphyr in the Telomere-to-Telomere consortium's assembly of the human X chromosome and the Genome In a Bottle Consortium's structural variant benchmarking data sets.

In parallel, Bionano has been nurturing the use of its system for clinical applications. "We've seen this before in clinical testing," with the introduction of PCR into clinical microbiology labs, Holmlin said. "This is the same type of transition we're trying to precipitate now in anatomic pathology around genetic analysis." The Saphyr is not cleared as a clinical device in either the US or Europe, so any assays are developed at customer sites and offered as laboratory-developed tests (LDTs.)

The firm is pushing for recognition of Saphyr's capabilities in two specific clinical fields: constitutional genetics and hematologic oncology. The firm estimates that there are about 2,500 cytogenetics labs worldwide that could adopt Saphyr for that purpose.

For constitutional cytogenetics, Bionano offers one workflow that replaces the need for several different disciplines, including microscopy-based ones. "Younger staff don't want to learn to look through a microscope," said Alex Hoischen, a researcher at Radboud University Medical Center in the Netherlands, who has tackled both areas with validation studies of Saphyr. Bionano's method is "very intuitive," he said, and suggested that Saphyr "could help educate a new generation of cytogeneticists."

Hoischen has been a key researcher in clinical validation studies for each of the clinical fields Bionano is targeting. In one study, his team analyzed 48 genomes from patients with acute lymphoblastic leukemia; in the other, he collaborated with French researchers from Cochin Hospital in Paris and Hospices Civils de Lyon to analyze 85 samples for 100 chromosomal aberrations seen in cytogenetic labs. Results from both studies have been posted on the BioRxiv preprint repository and are close to being submitted for peer-review, Hoischen said. He noted that he does not have any stock or other personal financial arrangement with the company; however, Bionano did supply a portion of the reagents for each study. 

In the leukemia study, the researchers looked at 37 "simple" cases and 11 complex ones. They found 100 percent of genetic aberrations in the simple samples and found all aberrations in 10 of the complex ones. The remaining sample was extremely complex, Hoischen said, adding that he believed advancements in coverage that boost sensitivity would detect the missed aberrations, if reanalyzed. He added that Saphyr also detected some aberrations that traditional methods did not pick up.

For the constitutional genetics validation study, the team analyzed 85 samples, chosen to represent "a good mixed bag of what a cytogenetic lab would see on a yearly basis," Hoischen said. Saphyr found 100 percent of the aberrations across all samples. "That is very good news," he said.

Hoischen added that in the constitutional cytogenetics study, the preprint used two different stringency filters to find aberrations. Two-step filtering is "cumbersome" and since then the team has improved the filter settings so that it can be done in one pass. This will be reflected in the manuscript submitted to peer review, he said.

In addition to the Europe-based validation study for constitutional genetics applications, Holmlin said a similar US-based study led by Columbia University is on track for peer-reviewed publication, though he did not say in which journal or how soon the firm expects publication.

Holmlin also noted that researchers are beginning to develop computational methods around Bionano data. He pointed to another BioRxiv preprint, from University of California, San Diego Professor Vineet Bafna, that introduces integrated analysis of optimal mapping and NGS data to resolve complex genomic structures in cancer. "When you see the bioinformatics community begin to take on our data type and develop unique methods around it, it really starts to accelerate the broader adoption and utility," Holmlin said.

As the study results roll in, Bionano has driven technology improvements. Saphyr is now capable of detecting low-abundance variants, Hoischen said, of down to 1 percent variant allele fraction, driven by improvements in coverage reaching 1,500x. "When you see the same event as few as three times, that should be sufficient to call the aberration," Hoischen said.

Holmlin noted that the firm has made advancements in sample prep, including solution-based prep for blood samples and, as of last month, the new Bionano Prep SP Tissue and Tumor kit for solid tumors and animal tissue.

"Earlier methods to purify long DNA involved agarose plugs and a tedious protocol with manual washing and digesting steps, taking up to three days to run four samples," Brandon LaBarge, a researcher at Penn State College of Medicine who was involved in the early-access program, said in a statement. These older methods provided inconsistent results, with several tumor samples failing altogether or generating limited throughput."

With the new kit, LaBarge's lab was "able to isolate ultra-high molecular weight DNA in less than six hours on six samples at a time, generating a consistent, high throughput on a variety of head and neck cancers."

Though Bionano customers appear poised to develop assays that are as good, if not better than traditional methods, there is still fogginess around how they will be paid for those tests, especially in the US.

In Europe, where the pace of adoption has been quicker, single-payor medical systems give healthcare institutions more freedom in choosing which technology they want to use, Holmlin said. "We can work directly with a lab to strike a deal where everything pencils out," he said. And regional accreditation allows other sites to bring in Saphyr in a similar context as the original LDT and unlocks the budget needed to operate the system.

In the US, "we still have to close the loop on how labs that run a test [on Saphyr] will get reimbursed," Holmlin said. "That's not something we as a research-use-only provider can work out."

However, Holmlin said he was hopeful that at some point in the future, clinical care guidelines on which variants to analyze could expand to include ones that only Saphyr can provide, which would help drive acceptance from payors.

While COVID-19 has prevented many customers from using their Saphyr platforms, some are turning their attention to the disease. Hoischen is also involved in a new initiative led by Augusta University to use Saphyr to detect structural variants in the human genome that could be relevant to COVID-19 disease severity. The consortium has filed its first grant application in the US and is looking to submit grants to international funding bodies.

"Initial results show that we do see a lot of structural variants in genes that play a role in this disease," said Sven Bocklandt, Bionano's senior director of scientific affairs and marketing. "We don't have results to disclose yet, but we do know that our instrument can detect these variants in genes that matter," he said, adding that the consortium aims to collect 1,000 samples for its cohort.

And while labs have been closed, Bionano is having success in engaging with researchers interested in Saphyr. "We've been able to get the message out and connect with folks, even though it's not in person," Holmlin said.

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