NEW YORK (360Dx) – Recent changes in physician behavior around monitoring patient response to therapeutic monoclonal antibodies (t-mAbs) is boosting demand for clinical testing of these drugs.
And this demand will likely continue to grow as new t-mAbs come to market and doctors continue to explore more customized dosing regimens, said Maria Willrich, an assistant professor of laboratory medicine and pathology and medicine at the Mayo Clinic.
Willrich noted the increase in t-mAb testing in a commentary published in November in Clinical Laboratory News.
Speaking to 360Dx, she said that the demand has come primarily from physicians using the TNFα inhibitors infliximab (marketed by Janssen as Remicade) and adalimumab (marketed by AbbVie as Humira) to treat autoimmune diseases, and particularly among gastroenterologists treating patients with conditions like ulcerative colitis or Crohn's disease.
"These are the most sold biologics in the world, so there are a lot of people taking these drugs, and it's not uncommon that after one or two years on the drugs, [patients] start losing their response to therapy," Willrich said.
This is typically due to the development of immunogenicity, wherein a patient develops antibodies against the drug, which reduces its effectiveness. To assess patient immunogenicity, labs can test for the levels of the t-mAb present as well as for the presence of antibodies against the drug.
Willrich said that around 99 percent of t-mAb testing orders at Mayo are to assess the loss of response to a particular drug.
More recently, labs have seen a move by some doctors toward what Willrich called "proactive monitoring" in which physicians try to use patient t-mAb levels to assess future outcomes.
"When we started in 2015 with our first test for infliximab, we would typically see maybe one or two test orders per patient, and then frequently that patient would be moved on to a different drug," she said.
With proactive monitoring, though, doctors are using serial testing to patient t-mAb levels with the goal of improving effectiveness.
"For instance, some have decided that at week six and week 14 of treatment with infliximab, patients [having drug levels] above a certain level is associated with positive outcomes in the future," Willrich said. "So they will try to keep their patients above a certain therapeutic level at those weeks and then adjust therapy there."
This is still an emerging area of research, but Willrich said she believed that the practice of more customized t-mAb dosing would likely expand given a number of ongoing trials looking at the ability of alternative dosing regimens to improve patient outcomes. This, in turn, would stimulate demand for more frequent t-mAb testing, she said.
She cited the example of the t-mAb eculizumab, which is sold by Alexion as Soliris and is used to treat rare conditions including atypical hemolytic uremic syndrome. The drug costs roughly $500,000 a year and patients are required to stay on it for their entire lives, a situation that inspired clinicians to look at whether smaller or less frequent doses could still be effective.
To support this effort, Willrich and her colleagues developed an assay for testing patient eculizumab levels, allowing doctors to monitor these levels as they experimented with custom dosing regimens.
Eculizumab "is prescribed rarely, only for very rare diseases, but I can see similar situations [involving more widely prescribed t-mAbs] coming up in the future," she said.
Mayo currently offers tests for infliximab, adalimumab, vedolizumab (a TNFα inhibitor sold by Millenium Pharmaceutical as Entyvio), and eculizumab.
Julio Delgado, chief medical officer at ARUP Laboratories likewise noted growing demand for t-mAb testing in light of concerns about patient immunogenicity.
He said that while doctors would typically increase dosing in patients who had stopped responding to TNFα inhibitors, research around immunogenicity published six to seven years ago suggested that testing of patient t-mAb levels and anti-t-mAb antibody levels could provide a more rational approach to dosing.
By testing for these molecules, clinicians were able to distinguish between patients who actually needed higher t-mAb doses and patients who had developed antibodies against a particular t-mAb and for whom an increase in dose would not improve response.
"People started reading these studies, and they started calling us saying, 'Hey, when are you guys going to have this test available?'" Delgado recalled. ARUP started offering tests for infliximab and adalimumab in 2013.
Like Willrich, Delgado said that more recently he has seen emerging demand for t-mAb testing not only to assess patient immunogenicity but to determine whether or not patients have the desired levels of the drug in their system.
"What was initially conceived as a test of whether a person had developed antibodies [against a t-mAb] is now being used by some clinicians just to make sure the patient is maintaining certain levels of a drug," he said.
He added, however, that more data is needed on what exactly these optimal drug levels may be, citing a recent recommendation from the American Gastroenterological Association Institute calling for t-mAb monitoring in patients being treated for active inflammatory bowel disease.
The AGAI recommends specific drug concentration targets for these patients, but Delgado said it was still unclear how generalizable that recommendation was beyond the study populations it has been tested in and how well different methods of assessing patient t-mAb levels correlate with one another.
"I don't think there is a lot of data currently that supports that a given patient has to have a certain amount of drug at a given time," Delgado said, but, he noted, that is where clinical practice appears to be moving.
"We're entering the era of therapeutic drug monitoring for these drugs," he said.
ARUP uses cell-based assays for its TNFα inhibitor testing, which covers infliximab and adalimumab. The company is also working to expand testing to biosimilars of those drugs.
The bulk of t-mAb testing is done using various immunoassay techniques, with outfits like Mayo, Quest Diagnostics, LabCorp, and Prometheus using different versions of this technology. Willrich said, however, that she expects mass spectrometry to play a larger role in t-mAb testing moving forward.
Because mass spec doesn't rely on affinity reagents, assay development times can be shorter than for immunoassays, which Willrich suggested could prove an advantage as clinicians become interested in monitoring a larger proportion of the 80-plus biologics approved for use in the US. She noted, though, that in some cases mass spec may not have the required sensitivity for t-mAb testing.
Willrich said that she and her colleagues at Mayo have used both triple quadrupoles and high-resolution instruments, including Thermo Fisher Scientific's Q Exactive and Sciex's TripleTOF 5600, for test development but that they were increasingly trending toward use of the high-res platforms, primarily the TripleTOF 5600.
She said that for infliximab, Mayo's test volumes have risen from around 300 a month when they launched testing to around 1,200 a month. Delgado declined to give ARUP's t-mAb test volume but said that after a rapid increase in demand following the introduction of testing, volumes have grown around 20 percent per year.
Willrich said that while t-mAb testing as whole is a potential growth area for clinical labs, she expects that growth of TNFα-inhibitor testing will level off as more labs bring such tests online and potentially some hospital systems bring testing in-house.
She added that point-of-care is another area of interest in t-mAb testing as it could help doctors better manage dosing by letting them assess drug levels immediately before an infusion, as opposed to having to wait several days to a week for results from a send-out test.
One company working in this area is San Diego-based Abreos Biosciences, which is developing point-of-care tests for t-mAbs in oncology, neurological disorders, and autoimmune disease. The firm uses peptide reagents called Veritopes that mimic the endogenous target of a given drug, allowing researchers to measure drug levels.
According to CEO Bradley Messmer, the company has developed lateral flow immunoassay devices that can be used much like a pregnancy test to measure t-mAbs at point of care.
Like Delgado, Messmer said that in most cases data is still lacking around what the ideal drug levels are for patients, but he said that as physicians explore different dosing regimens "a feedback loop" will develop that will help establish those levels.
In the meantime, he said, Abreos is "prioritizing markets here we feel like the physicians already kind of know what to do [in terms of dosing]."
One area of focus for the company has been testing natalizumab levels (marketed by Biogen as Tysabri). Natalizumab is used for treating multiple sclerosis but has, in some patients, increased the risk of progressive multifocal leukoencephalopathy, a serious and often fatal brain infection. Data from Biogen has indicated that patients receiving the drug less frequently have a lower risk of that side effect, which Messmer said has created demand for a test to help manage dosing.
Abreos currently offers a laboratory-developed test for natalizumab and is in what Messmer said is the "late prototyping stage" in its POC program.
He said that from a technical standpoint, developing POC tests for t-mAb monitoring is not especially difficult given that many of these drugs are given at fairly high doses and that a semi-quantitative result may be sufficient for informing treatment decisions.
More of an issue, Messmer said, is the economic side of the equation, and particularly the challenges around reimbursement that many diagnostic developers have struggled with.
"It takes a long time to get a novel test to where it can be confidently reimbursed at a set price point," he said. "And so how do you get a physician to buy a point-of-care test without knowing if he is going to get reimbursed for it?"
Meanwhile, "there is demand from payors to see real world evidence that these tests provide value, but to get the investment to develop that clinical data set without knowing you have a buyer at the end is challenging," he added. "So it's a little bit of a chicken-and-egg problem."