After nearly five long years of raising cash and completing additional clinical trials needed to win limited coverage, Integrated Diagnostics Inc. (Indi) said it will be the first company to introduce a liquid biopsy molecular diagnostic test for lung cancer in the US.
Indi's CEO Al Luderer said the company's second-generation Xpresys Lung (XL2) CLIA laboratory test is designed to help pulmonologists in the challenging task of identifying lung nodules that have a high probability of being benign; and thus, avoid unneeded, costly, invasive procedures that put patients at risk for complications.
"It has taken us $80m to get to this point and we still have a long way to go," Luderer told Medtech Insight. Indi launched the first-generation Xpresys Lung test in 2013. But when CMS denied coverage for that test, asking for more clinical data, Luderer quickly responded by pulling back the sales force, making the company small and shifting the focus toward completing clinical trials. He realized that patients weren't likely to pay Indi's asking price of $4,250 per test despite the company's efforts to offer financial assistance for those who needed it.
Today, things are looking up again.
Last December, the CMS provided Indi local coverage for XL2 for managing of a lung module between 8mm and 30mm in diameter in patients 40 years or older and with a pre-test cancer risk (as assessed by the Mayo Clinic Model for Solitary Pulmonary Nodules) of 50% or less with the intended use for physicians to identify those lung nodules that have a high probability of being benign. These patients would then be candidates for further observation using non-invasive computed tomography (CT) instead of surgery or biopsy.
"It took us four-and-a-half years to get enough prospective data to validate the second-generation product and submit it," Luderer said. "This is why no one is investing in molecular diagnostics. To decipher the clinical diagnostic science behind the disease and to then get coverage is extraordinarily difficult and it's not a predictable path."
"It took us four-and-a-half years to get enough prospective data to validate the second-generation product and submit it," Luderer says. "This is why no one is investing in molecular diagnostics. To decipher the clinical diagnostic science behind the disease and to then get coverage is extraordinarily difficult and it's not a predictable path."
Now that Medicare reimbursement is secured, the next big hurdle is to get pulmonologists' nod of approval for the test, Luderer said.
"Our largest challenge to date is to get physician adoption and getting the word out that this is the best way to practice," he said.
Luderer said while it's too early to comment on the specific marketing strategy, the company's sales reps will likely focus on geographic areas around centers of excellence and work with their established clinical collaborators to better understand their local areas before expanding the sales reach.
A major selling point will be the negative predictive value of 98% XL2 has demonstrated in clinical studies, which is a very low error rate in clinical trials, he noted. The test itself is a negative predictor (a rule-out test) in that when a person presents with nodules on a scan, it will determine if the nodules are benign rather than cancer, but if cancer is present, it will not confirm a cancer diagnosis.
Noise Vs. Information-Rich Proteins
Seattle, Washington-based Indi grew out of Seattle's Institute for Systems Biology and the California Institute of Technology, co-founded by biotech veterans Leroy Hood, David Galas, Paul Kearney and Jim Heath in 2009. To date, the company has raised $80m from investors InterWest Partners, Britain’s Wellcome Trust, BioTech Cube, Baird, CD Ventures and Alexandria.
According to Luderer, the founders of the company had a keen interest in liquid biopsy and understanding how proteins change in disease.
"Using multiple reaction monitoring (MRM) mass spectrometry, we were able to carefully look at the difference between early-stage cancer and benign disease," he said. "There are proteins in high abundance and many more proteins that are in low abundance in blood – we don’t know much about the low abundance proteins – so what we sought to do was to look at thousands of low abundance proteins that might relate to a particular pathology (in this case lung cancer)."
MRM mass spectrometry was pioneered by Hood's institute and it was his vision to filter through what Luderer calls "proteomic noise" and identify the "information-rich" proteins that are key to lung tumor functions.
The second version of Xpresys Lung is a proteomic risk predictor that integrates the expression levels of two proteins and is a refinement from the first version in that it incorporates five clinical risk factors – nodule size, age, smoking history, nodule location and nodule spiculation, according to CMS' Local Coverage Determination letter on Xpresys Lung.
"Nodules get reported all the time by radiologists and usually are referred to pulmonologists (for further evaluation)," Luderer explained. "Every year, some three million nodules are discovered in the lung in the US (the majority of which are Medicare-age patients of 65 years and older) and the question and the real problem physicians face when a nodule presents is to find the real cancer patients." He noted that about 220,000 patients are identified as lung cancer patients every year in the US.
"Nodules get reported all the time by radiologists and usually are referred to pulmonologists (for further evaluation)," Luderer says. "Every year, some three million nodules are discovered in the lung in the US (the majority of which are Medicare-age patients of 65 years and older) and the question and the real problem physicians face when a nodule presents is to find the real cancer patients."
Most nodules are found incidentally rather than by lung cancer screening.
Typically, when lung nodules are detected through a CT scan, physicians can't reliably distinguish between benign and malignant nodules in most cases. The American College of Chest Physicians (ACCP) guidelines for lung nodule management states that it is "nevertheless important to estimate the clinical probability of malignancy before ordering imaging tests or invasive biopsy procedures."
Doctors look at the size of the nodule, among other factors, to create risk stratification groups that put patients into low, intermediate and high-risk groups. For instance, if nodules are less than 8mm in diameter, they are typically considered benign. Then the patient is put on "watchful waiting" – where they will do follow-up CT scans to watch for growth. High-risk groups will generally go directly to surgery. Intermediate-risk patients often enter the "diagnostic odyssey" where patients first do a PET scan, and if that is negative, will be followed with CT scans. A positive PET scan is followed by surgery or biopsy, but here false positive results can pose more problems, Luderer said.
Indi found through their own observational studies of 18 community practices and 377 patients, that about 35% of patients who get nodules removed under the premise that it's cancer are benign. The study found that the surgery rate was the same for low, intermediate and high-risk patients; and despite the low risk, 28% of patients had biopsy and 17% had surgery.
Luderer said that XL2 can prevent many of these unnecessary and often risky surgeries and biopsies. He said the real dilemma are the intermediate-risk patients with nodules sized between 8mm and 30mm, of which there are at least 600,000 cases a year. He puts the marketing opportunity at $1bn.
"It's a blockbuster market," he said. "It always has been, but nobody realized it, because no one has been able to address it and run a test that actually works."
That said, Luderer is also the first to admit that getting buy-in from pulmonologists will not be easy.
"Everybody wants an early cancer diagnostic, but it's very difficult to actually sell it," he said. "What you run into is physicians who never had a test like this, because it was never available and you need to show them what the data says and that this will really improve patient care in your practice."
With the marketing plans of XL2 in full swing, Luderer said in the next two to four years, Indi hopes to migrate XL2 into an antibody format, which would allow the company to sell the product in geographic areas that don't have a CLIA-reference lab structure like the US. He points to European countries and the Asia Pacific region.
To make the conversion would require that the company converts the existing measurement platform to an anti-body detection platform. This would take years and money. He said the idea would be to create antibody-based test kits that could be marketed with a partner and sold to hospital laboratories.
"This would be an ideal way to franchise the technology," he said.
Europe, he noted, is known for having varying requirements for testing, depending on the country. Here, the company may partner with an IVD company where Indi would provide the kit that would then run on an immunoassay platform in a clinic. Similarly, in Asia, in particular China, CLIA-waived labs are in their infancy, which opens a window of opportunity to provide large hospitals with the antibody-based kits that are used in imaging tests.
Luderer is also the CEO of Indi Molecular, an independent company, that was spun out of Indi Diagnostics in 2013 with technology from the California Institute of Technology. It uses "click chemistry," a synthetic process that allows scientists to permanently join together molecular components. The company recently raised $11.5m in a Series C round to accelerate its PCC platform development.