NEW YORK – Harbinger Health has staked a claim as yet another challenger in the push to develop and implement multi-cancer blood-based screening for an asymptomatic population.
A product of Flagship Pioneering, the venture capital/tech development firm that backed SARS-CoV-2 vaccine-maker Moderna, Harbinger has been operating in stealth mode for the past few years on early cancer biomarker development and initial validation studies.
In late June, Harbinger announced it had partnered with Sarah Cannon Research Institute to begin a 10,000-participant case-control clinical study — an important next step to further validate and develop its assay.
Stephen Hahn, a former oncologist who briefly served as commissioner of the US Food and Drug Administration under the Trump Administration, is the firm's CEO.
In an interview this week, Hahn said that Harbinger believes it has a unique approach to detecting signals from the earliest moments of cancer development that will allow it to compete in a field where several companies are already conducting registrational trials for FDA submission, and one firm, Grail, is already offering its test clinically.
Hahn declined to provide details on Harbinger’s proprietary approach apart from the fact that it involves DNA methylation and relates to some biological underpinning of the transition from normal cell to malignant cell, potentially before such cells even begin to clump together, let alone spread and eventually metastasize.
Hahn also suggested this "biological signal" is relatively specific and may not require broad sequencing to identify methylation profiles over a large portion of the genome, as do many of the current technologies being advanced.
"When I was an oncology fellow 30 years ago, if I had told someone in the oncology clinic, 'we're going to have a … test that detects circulating tumor DNA in your blood,’ [they'd] have thought I was crazy,” he said. “Now it's a little bit of old news that you can detect tumor DNA in blood so what I think gives us an advantage is the ability to identify a biological signal … that is associated with the very earliest points in oncogenesis [and] … one where we know where to look, so we can be very targeted."
He further noted that the company strives for its assay to be “a low-cost initial screening test that has a very high negative predictive value."
Hahn said he spent many years as a skeptic of cancer screening, "not because I don't believe that diagnosing cancers early is better. I do, and every piece of data we have has shown that if you diagnose a cancer [at] stage I, at stage II, it's better than if you're diagnosed with stage IV." But he is cognizant of the challenge in translating early detection into improvement of clinical outcomes. Despite that skepticism, Hahn said, he has been persuaded by the unique ability of the Harbinger platform and its performance specifically in stage I and II cancers.
He said that the underlying biology of Harbinger’s method revolves around “how cancer forms, what's that related to, and how that relates to the hallmarks of cancer. And for me it was an ‘Aha!’ moment. … This biology makes sense to me, and it makes sense to me that it would be present at the earliest stages and throughout cancer," he added.
Although the company has not yet published any of its data, Hahn said it includes studies of about 1,000 cancer cases and controls across 20 cancer types.
The new validation study with Sarah Cannon should ramp up over the next 12 to 18 months, he said, with a major goal being the recruitment of a diverse population.
"We really felt strongly about going into the community, which is a real strength of Sarah Cannon," Hahn said. "We are being intentional, and we are very focused on making sure that we engage from the beginning communities that aren't typically involved."
According to Hahn, the next steps will be to take the resulting data and roll out a test, or series of tests, that Harbinger can then study in a registrational trial to support a bid for premarket approval by the FDA. At the same time, the company also believes real-world evidence will be key, so it may also launch clinical testing ahead of FDA approval.
"We are committed to going to the agency because these are high-risk tests. These are big diagnoses that are made. But we need to see how this performs in the real world … so that it's clear what to do with the result," he said.
"I can tell you from the practitioner side of things, if you're not helping doctors out — not just convincing them that the science is right and that the data are supportive — but also saying 'Hey, this is what we think you ought to do and here's why,' then you're not going to be successful in terms of adoption."
In terms of test content, Hahn said that there could be a range of options for how it launches its technology clinically. The nature of the signals it is targeting is such that Harbinger has the option for multi-cancer early detection, single cancer tests, or bundled subsets.
Persuading the FDA, clinicians, and insurers is no small task, Hahn added.
Skeptics of cancer screening, or even any disease screening, often highlight the issue of lead time bias. "The idea is that … a person will die in the future at the same point, whether you diagnosed their cancer in December or the following April," Hahn said. But he argued that there is good evidence that screening modalities like mammogram and colonoscopy, despite their shortcomings, do improve cancer-specific mortality.
Something that could help as well is the ability to differentiate indolent and aggressive cancers. Citing the example of PSA screening in prostate cancer, he said that at the end of the day, what clinicians need is to be able to "treat those who do need to be treated and watch those who don't."
"Arguably, we've done a better job in the PSA prostate cancer area more recently, but this is likely true for almost every solid cancer, that there are cancers that we identify that don't need to be treated," Hahn added.
"We think because of the relationship of [the biology we are targeting] to oncogenesis and the fact that there is both a quantitative and qualitative aspect to this, that we are going to be able to help clinicians figure out the indolent versus aggressive, and our preliminary data definitely support this," he said.
According to Hahn, Harbinger plans to conduct longitudinal studies focusing on both the issue of lead time bias and overdiagnosis. "It's a long haul, but just like with any other biomarker-driven approach, if your underlying biomarker is related mechanistically to the biology of the process, you've got a leg up," he said.
Early data from other players in the space provide some support for this optimism. For example, researchers from Grail have analyzed data from their studies that seem to indicate that the firm's Galleri test preferentially detects tumors known to be more aggressive.
"There is biological, clinical, scientific plausibility there," Hahn said. "And listen, we can throw our hands up in the air and say it's a tough problem and continue to diagnose patients with stage III and stage IV disease. Or we can try to solve it."
Looking even further into the future, Hahn said that Harbinger believes its approach could potentially be tuned to detect not just signs of oncogenic transformation but also its precursors.
Some of these are known in oncology already, and some, such as adenomas in colorectal cancer, are even considered intervenable. But for many other tumors that are rarely detected before they reach late stages, assessment and treatment of pre-cancer dysplastic lesions just aren't a major part of clinical care.
That, he said, “opens up a whole avenue of potential therapeutics [and] a new way to stage and diagnose patients and to make a significant impact."
Citing heart disease as an analogy, Hahn noted that earlier generations lived in fear of dropping dead of a heart attack. The field had discovered hypertension and high cholesterol as risk factors, but for a long time there were no known interventions. "Now we know that things like statins [and] hypertensive medications can improve cardiovascular mortality and that fear has been [ameliorated]. … Most people don't get afraid to get a cholesterol test or blood pressure check because there are ways we can intervene, preempt. We need to do the same thing with cancer," he said.